3-hydroxy-1, 5-bis-dehydro steroids and methods for their manufacture



United States Patent 3,332,967 3-HYDROXY-1,S-BIS-DEHYDRO STEROIDS AND METHODS FOR THEIR MANUFACTURE Eugene P. Oliveto, Glen Ridge, N.J., and Masato Tanabe, Palo Alto, Calif., assignors to Schering Corporation,

Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Mar. 7, 1963, Ser. No. 263,441 11 Claims. (Cl. 260397.45)

This invention relates to a novel class of cyclopentanophenanthrene compounds and to methods for their manufacture, including intermediates produced thereby.

More particularly, this invention relates to 1,5- bis-dehydro-steroids having a hydroXy group at C3, including esters and derivatives thereof, which are therapeutically valuable per se and are also useful as intermediates in preparing other valuable compounds.

Illustrative of the novel S-hydroxy-LS-dienes and derivatives thereof of our invention are compounds such as those of the following structural formula:

wherein A is a member selected from the group consisting of hydrogen, (I'LOPIOWCI alkyl), (HIS-lower alkyl), (preferably methyl), lower alkylene (preferably methylene), (H,a hydroxy), and (H,u-lower-alkanoyloxy); B is a member selected from the group consisting of hydrogen, lower alkyl (preferably methyl), and halogen (preferably fluorine); R is a member selected from the group consisting of hydrogen, lower alkyl, and acyl; Y is a member selected from the group consisting of hydrogen, keto (H,/3-OR'), (H,nc-OR'), and (EB-halogen), R being a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consisting of hydrogen and halogen, and when Y is (I-La-OR'), X is hydrogen, and when Y is (Hp-halogen), X is halogen, and X and Y together are members selected from the group consisting of an epoxy and a double bond; and Z is a member selected from the group consisting of CH2Q,

R" being a member selected from the group consisting of hydrogen and an acid radical of a carboxylic acid having up to 18 carbon atoms; D being a member selected from the group consisting of hydrogen, lower alkyl, ethinyl, halogeno-ethinyl, and al'kyl-ethinyl; V being a member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy; and Q is a member of the group consisting of hydrogen, hydroxy, acyloxy, and halogen. By lower alkyl is contemplated hydrocarbon radicals having up to four carbon atoms, thus including methyl, ethyl, n-propyl, iso-propyl, n butyl, sec-butyl, and tertbutyl radicals.

Illustrative of the carboxylic acids contemplated at C-3 and C-17, and, in the case of pregnanes, at C-2l, are lower alkanoates such as acetate, propionate, caproate, tertiarybutylacetate, cyclopentylpropionate, di-

D, and

3,332,967 Patented July 25, 1967 methylacetate, trimethylacetate, and phenoxylacetate; aryl esters such as benzoate, nicotinate, thiophene carboxylate; and esters from dibasic organic acids such as succinate, phthalate, and sulfobenzoate. Also included are the alkali metal salts of the dibasic carboxylic acid esters such as, for example, the 3-sodium hemisuccinate of l7a-methyl-1,5-androstadiene-3,17,8-diol.

In addition to carboxylic acid esters such as described above, included among the acyl groups at C-3 and, in the case of pregnadienes, at C-21 of the 3-hydroxy-1,5- bis-dehydro steroids of our invention are inorganic acid esters such as sulfate and phosphate.

In the structural formula shown above, the bond at C-3 is designated by a wavy line to indicate that both the a and p isomeric forms at this position are encompassed by this invention. When a compound name does not specify a particular configuration (i.e., a or p) at C-3 or C-16, e.g., 1-6-methyl-1,5-pregnadiene-3,l113,

17a,21-tet10l-20-011e, it is understood that both the a and ti isomeric forms are included, e.g., l6a-methyland 16,8- methyl 1,5 pregnadiene 3B,11;3,17a,21 tetrol 20 one and 16a-methyland 1GB-methyl-l,5-pregnadiene-3a, l1p,17a,2l-tetro1-20-one.

Among the therapeutically active, novel steroids of our invention are 3-hydroxy-1,5-androstadienes such as those defined by general Formula I wherein Z is 0 OR" 5 or D R and D being defined as hereinabove (except those compounds wherein X and Y is an epoxy or a double bond, valuable mainly as intermediates), which are superior anabolic agents having a favorable anabolic/ androgenic ratio, i.e., they are potent anabolic agents having a minimum of androgenic activity. Our 3-hydroxy- 1,5-androstadienes may be advantageously used in place of anabolic/ androgenic agents used in known pharmaceutical preparations with the advantage that lower doses of the 3-hydroxy-1,5-dienes may be used in view of their superior activity.

Typical 3-hydroXy-1,S-androstadienes of our invention valuable as anabolic agents are compounds such as 1,5-androstadiene-3B-ol-17-one, 1,5-androstadiene-3 fi,17fl-diol, 17a-methyl-1,5-androstadiene-3 5,17/3-dio1, 9a,1lp-dichloro-Noe-methyl-1,5-androstadiene- 3,8,17B-diol, 17a-ethinyl-1,S-androstadiene-B,17,3-diol, 17a-ohloroethinyl-1,S androstadiene-I:,-17p-diol,

the 3a-epimers of the foregoing and the 3-acetate esters thereof. v

In addition, 17a-alkynyl derivatives defined by the general Formula I such as 17ot-ethinyl-1,5-androstadiene-3 17,8 diol and s halogenoethinyl 1,5 androstadiene- 3,17fl-di01 possess progestational and anti-fertility properties.

The" preferred species of our invention are the anabolic/androgenic agents, 17a methyl 1,5 androstadiene-3B,l7/3-diol and S-esters thereof (e.g., the S-pnopionate, 3-decanoate, and the 3-enanthate thereof) which are orally efiective and advantageously and surpisingl) have been found to possess a greatly enhanced and favorable anabolic/androgenic activity ratio over that of the known-orally effective anabolic agent, 17u-methyl-1,4- androstadiene-17/8-ol-3'one.

Our anabolic/ androgenic agents are preferably administered orally in daily doses ranging from about 0.5 to 20 mg. depending on the nature and severity of the patients illness. Convenient composition forms for oral use are tablets of unit doses of 0.5 mg. and 5 mg.

In general, the pharmaceutical formulations of our 3- riydroxy-1,5-androstadienes are prepared utilizing pro- :edures known in the art. In formulating these pharma- :eutical compositions, a novel compound of this invention, e.g., 17-a-methyl-1,5-androstadiene-35,175-diol, is lsually compounded with an excipient which is edible and :hemically inert to the aforenamed 1,5-androstadiene. Excipients such as lactose, sucrose, starch, pre-gelatinized LtfiI'Ch, gum arabic, gum tragaccenth or mixtures thereof nay be used, usually in admixture with an additive such 1s magnesium stearate, talc, cornstarch or the like.

Oral pharmaceutical composition forms other than ablets may be used. Thus, in general, fine powders or granules of 170: methyl 1,5 androstadiene 35,175- liol or an ester thereof may contain diluents and dispersng and surface active agents and may be presented in a yrup, or in capsules or cachets in the dry state or in a ion-aqueous suspension, when a suspending agent may re included in tablets, when binders and lubricants may me included; or in a suspension in Water or in a syrup or u an oil, or in a water/oil emulsion when flavoring, preerving, thickening, emulsifying agents may be included. ."he granules or the tablets may be coated.

The novel 2l-desoxy-3-hydroxy-1,5-pregnadienes of our avention, such as are exemplified by the compounds dened by the general formula when Z is CHzQ (i= 6... 2 being hydrogen and halogen; V being hydrogen, hyroxy, and lower alkanoyloxy (except the 95,115-epoxynd 9,1l-dehydro-derivatives, valuable as intermediates) 1 general possess pr-ogestational activity and as such may e used in a similar manner, and for alleviating the same isorders, as known progestational agents such as proesterone, ethisterone, and the like. Additionally, 21-haloeno-17a-hydroxy-1,5-pregnadiene-3-ols of our invention ossess anti-inflammatory activity.

Representative of 2l-desoxy-1,5-pregnadiene-3-ols of the eneral Formula I, which are therapeutically active as ascribed above, are 1,5-pregnadiene-35-ol-20-one, 1,5- regnadiene-35,17a-diol-20-one and the 3,17-diacetate iter thereof, 21 fiuoro 1,5 pregnadiene 35,170: diol- 3 one, 90:,115 dichloro 17cc acetoxy 1,5 pregnaiene 35 o1 20 one and the 3a-epimers thereof.

Representative of 21 oxygenated 1,5 pregnadiene- -ols as defined by the general formula I when Z is being hydroxy or an ester thereof; V being hydrogen,

, droxy, and lower alkanoyloxy, are compounds such as 5 pregnadiene 35,115,21 triol one; 1,5 pregtdiene 35,115,17a,21 tetrol 20 one; and 1,5 pregidiene 35,17a,21 triol 11,20 dione and their 6- ethyl-, 6 fluoro-, 16 methylene-, 16a methyl-, 16-5- ethyl-, 16a-hydroxy-deriva-tives thereof as well as 90:- tlogene-derivatives such as t-fluoro-1,5-pregnadiene-35,17a,21-triol-l 1,20-dione, t-fluoro-l ,5-pregnadiene-35, 1 15, 1711,21- tetrol-ZO-one, t-fluoro-16-rnethylene-1,5-pregnadiene-35,1 1,8,

17a,21-tetrol-20-one, 1,1l5-dichloro-1,5-pregnadiene-35,1704,21- triol-20-one, .-fluoro-1Ga-methyl-1,5-pregnadiene-35,l 15,17u, 21-tetrol-20-one, .-fiuoro-16a-methyl-1,5pregnadiene-35, 17a,2 1- triol-11,20-dione, methyl-9a-fluoro1,5-pregnadiene-3 5,115,711- 21-tetrol-20-one,

4 6,16a-dimethyl-9ot-fluoro-1,5-pregnadiene-35,

1l5,17u,21-tetrol-20-one, 6,9a-dilluoro-1,5-pregnadiene-35,115,17a,21-

tetrol-ZO-one,

and the 3a-epimers of the foregoing.

The 11 substituted 2O keto 1,5 pregnadiene 3- ols (except the 11cc hydroxyand 95,115 epoxy pregnadienes which are valuable mainly as intermediates) which also possess at least one hydroxyl group at the aand 21-positions, possess cortical activity. In addition, some of these compounds, e.g., the 3(a and 5),17a,21-trihydroxy-1,5-pregnadienes, possess anti-inflammatory activity and are used in the same manner as known corticoids such as prednisone and prednisolone.

In general, the pharmaceutically active 3-hydroxy-1,5- pregnadienes of our invention have an activity similar to the corresponding 3-keto-1,4-pregnadiene and may be administered in similar pharmaceutical forms and for the same indications for which the 3-keto-l,4-pregnadiene would be applicable. For example, 1,5 pregnadiene-35, 1l5,17o,21-tetrol-20-one and esters thereof possess antiinflammatory activity similar to that of prednisolone and may be administered intramuscularly as the 3,21-diacetate in an aqueous suspension; orally in the form of tablets or capsules; or topically as a cream to which may be added other active ingredients such as neomycin sulfate, or in the form of opthalmic suspensions or as nasal sprays. In each instance, the pharmaceutical preparations are prepared according to procedures well known in the art.

The novel 3-hydroxy-1,5-dienes of our invention, e.g., 17a-methyl-1,5-androstadiene 35,175 diol and the 30:- epimers thereof, are conveniently prepared by our process from the corresponding 3-keto-l,5-dienes, e.g., 17w methyl-1,S-androstadiene--ol-3-one, upon reduction by means of an alkali metal aluminum or borohydride (lith ium aluminum hydride, sodium borohydride, etc.), or a metal alkoxide in the corresponding alcohol (e.g., aluminum isopropoxide in isopropanol or aluminum tertbutylate in tert-butanol), whereby there is formed both the 35- and 3a-hydroxy isomers, e.g., the anabolic agents, l7a-methyl-1,5-androstadiene-35,175-diol and 17a-rnethyll,5-androstadiene-3a,175-diol, separable via fractional crystallization and chromatographic techniques. Usually the 35-hydroxy isomeric form predominates and is isolated and purified by crystallization. The 3a-hydroxy isomeric form may then generally be separated from the mother liquor of the 35-01 by chromatography utilizing procedures well known in the art.

Prior to reduction of a 3-keto-l,5-diene to a 3-hydroxy- 1,5-diene by the above-described process, any ketones present at C-17 or C-20, in the case of pregnadienes, should preferably be protected by a group such as an ethylene ketal or, in the case of those starting steroids having a cortical side chain, a bis-methylenedioxy derivative. Thus, for example, the 17,20;20,2l-bis-methylenedioxy derivative of 1,5-pregnadiene-l15,17a,21-triol-3,20-dione is reduced with lithium aluminum hydride to the 17,20; 20,21-bis-methylenedioxy derivative of 1,5-pregnadiene- 3(a and 5),115,17a,21-tetrol-20-one, which upon mild acid hydrolysis will yield l,5-pregnadiene-3(a and 5), 1l5,l7a,2l-tetrol-20-one, separable via crystallization and chromatographic techniques to the 304- and 35-hydroxy isomers, both of which are valuable as anti-inflamatory agents.

While it is preferable to protect a reactive ketone other than at (3-?! prior to reduction according to our process, the more hindered, less reactive ketones such as at C11 need not necessarily be protected depending on the reaction conditions. For example, an ll-ketone group will not be affected if our process is carried out utilizing sodium borohydride at room temperature or aluminum isopropoxide in isopropyl alcohol. In addition, if the ZO-ketone in a cortical side chain is sufliciently hindered, such as by the presence of a 17,2l-acetonide or 17,21-diester, reduction with sodium borohydride oraluminum isopropoxide according to our process will convert the 3-keto to a 3- hydroxy without reduction of the 20-ketone. Additional- 1y, a ketone such as at C-17 may advantageously be left unprotected if a hydroxy vfunction is desired. For example, to prepare 1,5-androstadiene-3fl,17fl-diol according to our process, one may reduce either 1,5-androstadiene- 3,17-dione or 1,5-androstadiene-l7fl-ol-3-one.

The starting compounds for our process thus may be any steroid having a 3-keto-A system in the A-ring with those compounds having a reactive ketone at C17 or,

'in the case of pregnadienes, at C-20 being preferentially protected as described hereinabove. Thus, suitable starting steroids include the 20-ketals and (in the case of corticoids) the 17,20;20,2l-bis-methylenedioxy derivatives of 3-keto-1,5-pregnadienes such as 17a-methy1-1,5-androstadiene-l7fl-ol-3-one, and

17-ethylenedioxy-1,S -androstadiene-3-one.

It is apparent from the foregoing that the 3-keto-A starting compounds of our novel process may be substituted at one or more carbons on the steroid nucleus, particularly at positions 6, 9, 11, and 16, which substituents are introduced by methods well known in the art.

The 3-keto-l,5-dienes useful as intermediates in our process are conveniently prepared from a 6-substituted intermediate (i.e., a 6-bromoor 6-alkanoyloxy-) of the corresponding 3-keto-1,4-dienes by reaction with zinc in alcohol or magnesium in ether according to procedures described in US. Patent No. 2,908,696. Alternatively and preferably, a 3-keto-1,5-bis-dehydro starting compound of our process, e.g., 17a-methyl-1,5-androstadiene-17B- ol-3-one, is prepared by reaction of the corresponding 3- keto-A steroid, e.g., 17a-methyl-l-dehydrotestosterone, with a reagent of the group consisting of an alkali metal acetylide such as sodium acetylide, an alkali metal alkylsubstituted acetylide such as sodium methyl acetylide, and alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide, or an alkali metal substituted alkyl derivative such as sodium triphenylmethyl, in a solvent which does not give up a proton according to procedures described in co-pending application, Ser. No. 251,744, of Masato Tanabe and Elliot L. Shapiro filed Jan. 16, 1963, now US. Pat. 3,127,428.

The ketone protective groups, e.g., ketals or bis-methylenedioxy functions, are preferably introduced into the molecule prior to the above-described conversion of a 3- keto-1,4-diene to a 3-keto-1,5-diene intermediate of our process. Thus, when preparing the novel 1,5-pregnadiene- 3 5,1lfi,l7a,2l-tetrol-20-one and 3ot-epimer thereof by our process, preferably there is first prepared by known procedures the bis-methylenedioxy derivative of prednisolone which, in turn, upon reaction with sodium acetylide in dimethylformamide, for example, is converted to the corresponding 3 keto 1,5-diene, 17,20;20,2l-bis-methylenedioxy-1,5-pregnadiene-11fiol-3-one. Reaction of the latter compound with sodium borohydride according to our process yields 17,20;20,21-bis-methylenedioxy-1,5-pregnadiene-3(a and ,8), llfl-diol of this invention which upon mild hydrolysis according to known techniques is conyerted to 1,5-pregnadiene-3 (a and p),11,B,17u,21-tetro1- '6 20-one, separable via chromatographic techniques into the 341- and 3/3-hydroxy isomers.

Similarly, l-dehydroprogesterone, upon reaction with ethylene glycol according to known procedures, yields 20- ethylenedioxy-l,4-pregnadiene-3-0ne which, when subjected to the action of sodium acetylide in dimethylsulfoxide according to the above-described process of Tanabe and Shapiro, is converted to ZO-ethylenedioxy-1,5-pregnadiene-3-one, convertible by reduction with sodium borohydride in water according to the process of this invention to 20-ethylenedioxy-1,5-pregnadiene-3(a and fl)-ol. Cleavage of the ZO-ketal is effected according to known techniques to obtain the free ZO-ketone compound of Formula I, 1,5-pregnadiene-3(m and p)-ol-20 one, separa-blevia crystallization and chromatographic techniques to the 30:- hydroxy and 3,8-hydroxy isomers.

Similarly, the 9 and 11, or the 11, and 16 substituted 3-hydroxy-1,5-dehydro-steroids of the general Formula I are preferably prepared from the corresponding 3-keto-1, S-dehydro steroid having the appropriate substituent present at the 9, 11, and 16 carbon atoms prior to reduction by means of a metal hydride or metal alkoxide. In turn, the appropriately substituted 3-keto-l,5-bis-dehydro intermediates are preferably prepared from the correspondingly substituted 3-keto-1,4- dienes by reaction with sodium acetylide in dimethylsulfoxide, for example. Introduction of ketone derivatives, or substituents at 9, 11, or 16 after conversion of a steroid to a 3-keto-l,5-diene or a 3-hydroxy-1,5-diene system may result in partial reversion to a 3-keto-1,4-diene system or low yields of substituted 3-hydroxy-1,5-bis-dehydro steroid.

In view of the foregoing, it is surprising that the 6- unsubstituted 3-hydroxy-l,5-dienes of Formula I, in addition to being therapeutically valuable per se are also valuable as intermediates in preparing other therapeutically valuable compounds, i.e., the 6-substituted 1,5-diene-3-hydroxy analogs as well as 6-substituted 3-keto-l,4-bis-dehydro steroids.

In the conversion of a 3-hydroxy-1,5-diene to a 3- keto-6-substituted-1,4-diene, the transformation is effected utilizing procedures analogous to known techniques. After protection of any ketones present at C-17 or C-20 (necessary only if a 6-alkyl is to be introduced via a Grignard reagent), selective epoxidation of the A -bond by means of a per-acid, followed by treatment of the resulting 5a, 6OL-6POXY with hydrofluoric acid or a Grignard reagent such as methyl magnesium iodide yields the corresponding 5ahydroxy-6,B-fiuoro or 5u-hydroxy-6fi-methyl-A -3/8-ol intermediate, respectively. Manganese dioxide oxidation oi the 3,B-hydroxy to a 3-keto group followed by dehydration of the 5a-hydroxy function with a reagent such as thionyl chloride in pyridine will yield the corresponding 3-keto-6fi-fluoroand 3-keto-6B-methyl-1,4-dienes, respectively. Epimerization to the Got-isomers may be effected with a base such as potassium t-butoxide in t-butanol to obtain the 3-keto-6e-tluoroand 3-keto-6a-rnethyl 1,4-

' diene, respectively.

In the conversion of a Z-hydrOXy-LS-die'ne to a 6-substituted, e.g., a 6-fluoroor a 6-methyl-3-hydroxy-1,5- diene, after epoxidation of the A -b0nd and treatment oi the resulting 50:,60: epoxy with hydrofluoric acid or a Grignard reagent, the resultant 5ot-hydroxy-6/3-fluoroo1 5u-hydroxy-6/3-methyl-A -3;3-o1 intermediates are esterifiec' at C-3 (acetic anhydride in pyridine, for example) prior tc dehydration of the 5u-hydroxy function with thionyl chloride in pyridine whereby is obtained the corresponding 3- acetoxy-6-fluoroand 3-acetoxy-6-methyl-1,5-diene, respectively.

By way of example, the 17,20;20,21-bis-methylenedioxy derivative of 1,5-pregnadie11e-3,l1B,17a,21-tetrol-20-onE is epoxidized on treatment with monoperphthalic acid tc give the epoxy derivative, 5u,6w-epoxy-17,20;20,2l-bismethylenedioxy-1-pregnene-3,1lfl-diol, from which bott the 6-methy1- and 6-fluoro-substituents may be introduced nto the molecule. Thus, the action of hydrofluoric acid )H the epoxy intermediate yields the 5a-hydroxy-6/3-fiu0ro ntermediate, e.g., 5a-hydroxy-6fl-fluoro-17,20;20,21-bisnethylenedioxy-1-pregnene-3,l1 B-diol; whereas, addition )f a Grignard reagent such as methyl magnesium iodide vith subsequent hydrolysis yields the 5a-hydroxy-6B- nethyl compound, e.g., 5oc-hydroxy-6p-methyl-l7,20;20, ll-bis-methylenedioxy-1-pregnene-3,11,6 diol. Oxidation If the 3-hydroxy function of the aforementioned SOL-hylroxy-6-substituted derivatives to a 3-keto group with a eagent such as manganese dioxide or chromic acid folawed by dehydration of the '5u-hydroxy function with a eagent such as thionyl chloride in a cold, basic medium, .g., pyridine, will yield the 3-keto-6/3-substituted-l.4- ienes, 6;8-fiuoro-17,20;20,21-bis methylenedioxy 1,4- regnadiene-1lfl-ol-3-one and 6B-methyl-17,20;20,21-bisiethylenedioxy- 1 ,4-pregnadiene-l lfi-l-3 -one, respective- The 6oc-substituted derivatives are prepared from the orresponding 6,8-substituted isomers upon treatment with base such as potassium t-butoxide in t-butanol. The 6aubstituted steroids thereby formed, e.g., 6a-fiuoro-l7,20; 0,2l-bis-methylenedioxy-1,4-pregnadiene-llfi-ol 3 one nd 6a-methyl-17,20;20,2l-bis-methylenedioxy-1,4 pregadiene-11fl-ol-3-one, are then hydrolyzed by means of queous formic or aqueous acetic acid to form the knOWn lerapeutically valuable compounds 6oc-flllOIOPI6dI1lSO- me and 6w-methylprednisolone, respectively.

Alternatively, ot-hydroxy-6 substituted intermediates repared as described above, i.e., 5u-hydroxy-6fi-fluoro-l7, D;20,21-bis-methylenedioxy-1-pregnene-3,11B diol and x-hydroxy-6fi-methyl-17,20;20,2l-bis-methylenedioxy 1- regnene-3,l1,B-diol, may be esterified at C-3 such as with :etic acid anhydride in pyridine, and the corresponding 3- :etate esters then dehydrated with thionyl chloride in a )ld, basic medium, e.g., pyridine, to obtain the 3-ace- Xy-6-substituted-1,S-dienes, e.g., 6-fluoro-l7,20;20,21-bisvethylenedioxy-1,5-pregnadiene-3,1lfi-diol 3-acetate and methyl-l7,20;20,21-bis-methylenedioxy-1,5-pregnadienellfi-diol 3-acetate. Hydrolysis under mild acidic contions will yield 6-fluoroand 6-methyl-1,5-pregnadienel 1,8, l7a,21-tetrol-20-one, respectively.

In an analogous manner, treatment of 5a,6a-epoxy-17, );20,2l-bis-methylenedioxy-1-pregnene-3, l 1 fl-diol with ldrochloric acid yields 5a-hydroxy-6fl-chlorol7,20;20, .-bis-methylenedioxy-1-pregnene-3,1 1 fi-diol. Acetylation C3 followed by dehydration at C5 with thionyl chlode and subsequent cleavage of the bis-methylenedioxy motion will yield 6-chloro-1,5-pregnadiene-3,1l/8,l7a,2ltrol-20-one 3-acetate.

The novel 3-acyloxy-1,5-dienes of our invention are nveniently prepared from the corresponding 3-hydroxy impound via conventional techniques, such as those uti- :ing an acid anhydride or an acid halide in pyridine. nus, for example, 17a-methyl-1,5-androstadiene-3B,17B- 01 upon treatment with acetic anhydride in pyridine at om temperature yields the corresponding 3-monoacetate ter; whereas, treatment at higher temperatures, e.g., C., for long periods of time will yield the correspondg 3,17-diacetate ester.

A mixed ester of a 3-hydroxy-1,S-bis-dehydro-anostane of our invention is conveniently prepared by st selectively esterifying the 3-hydroxy group and then terifying other hydroxyl groups present in the molecule. ar example, 17a-methyl-l,S-androstadiene-Blfl,17,8-diol on reaction with acetic anhydride in pyridine at room nperature is converted to the 3-mono-ester, 17u-meth- -1,5-androstadiene-3B,17fl-diol 3-acetate. The 17-hyoxyl function may then be esterified such as with nzoyl chloride in pyridine at room temperature or with opionic acid anhydride in pyridine at elevated temperares (i.e., about 80100 C.) to obtain the respective xed esters, i.e., 17u-methyl-1,5-androstadiene-3fl,17B-

)l 3-acetate 17-benzoate and l7a-methyl-L5-androsta- :ne-3B,l7fl-diol 3-acetate 17-propionate, respectively. When our process, whereby a 3-keto-l,5-diene is reduced to a 3-hydroxyl,5-diene, is carried out utilizing an alkali metal borohydride or a Meerwein-Ponndorf-Verley reducing agent (i.e., a metal alkoxide) as the reducing agent, any ester group present in the starting compound generally remains unchanged. Thus, for example, 1,5-androstadiene-17B-ol-3-one l7-caproate, upon treatment with aluminum isopropoxide in isopropanol according to our process, will yield 1,6-androstadiene-3/8,l7fi-diol 17- caproate and the 3a-epimer thereof. Reaction of the 30cand 3,8-hydroxy epimers (after separation thereof as described hereinabove) with an esterification agent, e.g., benzoyl chloride in pyridine, will yield mixed esters, e.g., 1,5-androstadiene-3B,17,8-diol 3-benzoate 17-caproate and the 3ot-epimer thereof.

Upon mild alkaline hydrolysis of a 3-acyloxy-1,5-diene of this invention, the ester group at C-3 is hydrolyzed without hydrolysis of ester groups of tertiary hydroxyl groups in the compound. For example, 17a-methyl-l,5- androstadiene-3fi,17,8-diol diacetate upon treatment with aqueous methanolic sodium carbonate at room temperature is converted to the l7-monoacetate, e.g., Not-methyl- 1,5-androstadiene-3/3,l7fi-diol 17-acetate. When more rigorous hydrolyzing conditions are used, for example, hot, aqueous methanolic sodium hydroxide, ester groups of tertiary hydroxyl groups may also be hydrolyzed.

Another method for preparing mixed ester derivatives of our 3-hydroxy-1,5-dienes, therefore, is by selectively hydrolyzing under mild acid conditions the 3-acyloxy group in a polyester of a compound of Formula I, e.g., 1,5-pregnadiene-3 8,l7ot-diol-20-one diacetate and re-esterifying the resultant 3-hydroxy diene, e.g., 1,5-pregnadiene-3fi,l7u-diol-20-one 17-acetate, with another acid reagent, e.g., succinic anhydride in pyridine, to obtain a mixed ester, e.g., 1,S-pregnadiene-Iifl,17a-diol-20-one 3- hemisuccinate 17-acetate.

The following are examples illustrating my invention. It is to be understood that the invention is not to be limited to the exact details of operation or to the exact showings and descriptions, as obvious modifications and equivalents will be apparent to one skilled in the art. The invention is, tllierefore, to be limited only by the scope of the appended c aims.

EXAMPLE 1 1,5-andr0stadiene-3-0l-1 7 -0ne (A) J7-ethylene glycol ketal of 1,5-androstadiene-3, 17-di0ne.-To ml. of dimethyl sulfoxide add 40 ml. of a suspension of sodium acetylide (20%) in xylene. To this stirred mixture add 5 g. of 17-ethylene glycol ketal of 1,4-androstadiene-3,l7-dione and continue stirring at room temperature for 20 minutes; then pour slowly into 1 l. of ice water. Separate the layers. Saturate the aqueous phase of the mixture with sodium chloride and then extract with methylene chloride. Combine the methylene chloride extracts with the original organic layer of the reaction mixture and wash with water, dry over magnesium sulfate and evaporate in vacuo to a residue of 17- ethylene glycol ketal of 1,5-androstadiene-3,17-dione. Purify by crystallization from acetone-hexane (containing a drop of pyridine).

(B) 17-ethylene glycol ketal of 1,5-andr0stadiene-3/3- 0l-I7-0ne and the 3ot-epimer thereof.Cool to about 10 C. a solution of 2 g. of l7-ethylene glycol ketal of 1,5- androst adiene-3,17-dione in 50 ml. of tetrahydrofuran; then add a solution of lithium aluminum hydride (0.75 g.) in 25 ml. of tetrahydrofuran while maintaining the temperature of the reaction mixture below 18 C. After one hour cautiously add ml. of acetone to destroy any excess lithium aluminum hydride; then add about 1 l. of water and boil the mixture until the temperature reaches 94 C. Cool the reaction mixture to 15 C. and filter the resultant solid of substantially 17-ethylene glycol ketal of l,5-androstadiene-3 x and ,6)-ol-17-one. Dry the solid and crystallize from aqueous methanol to obtain l7-ethylene glycol ketal of 1,5-androstadiene-3B-ol-l7-one. Evaporate the aqueous methanol filtrate in vacuo to a residue of substantially 17-ethylene glycol ketal of l,5-androsta .diene-Ba-ol-17-one. Purify by dissolving in methylene chloride and chromatography on Florisil,.eluting with methylene chloride with increasing amounts of acetone.

(C) 1,5-andrstadiene-3fl-ol-17-0ne and 1,5-wnarostadienre-3a-o l-17-onte.Diss0lve 1 g. of 17-ethylene glycol ketal of 1,5-androstadiene-3/8-ol-17-one in ml. of aqueous methanol (10 ml. methanol/1 ml. Water), add 1 ml. of 10% aqueous sulfuric acid, and allow the mixture to stand at room temperature for 6 hours. Add water, then 'filter the resultant precipitate of 1,5-androstadiene-3B-ol- -17-one.

In a similar manner, the 17-ethylene glycol ketal of -,1,5-androstadiene-3a-ol-17-one is treated with dilute sulfuric acid in aqueous methanol and there is obtained 1,5-

androstadiene-3a-ol-17-one.

EXAMPLE 2 1 7(l-mlelhyl-1 ,5-androstadiene-3J 7 B-diol (A) 1 7a-methyl-1 ,5 -androstadiene-1 7 B-0l-3-0n'e.-Add 44 ml. of a suspension of 20% sodium acetylide in xylene to 100ml. of dimethylsulfoxide in which is dissolved 5 g. tot 17u-methyl-1,4 androstadiene-17/3-ol-3-one. Stir the reaction mixture at room temperature for approximately 30 minutes, then pour the mixture slowly into 1.5 l. of ice water. Add sodium chloride to this mixture until the aqueous phase is saturated, then extract with methylene chloride. Combine the methylene chloride extracts, wash with water, then dry over magnesium sulfate and evaporate in vacuo on a steam bath to a crystalline residue of about 5 g. of 17a-methyl-1,5-androstadiene-17,B-ol-3 one. Purify by crystallizing from acetone-hexane.

(B) 17a-methyl-LS-androstadiene 3,8,176 diol and 17a-methyl-1,S-androstadiene-hJ7 9-di0l.Co0l to 2 C. ,a solution of 23.4 g. of 17u-methyl-1,5-androstadiene- 17}8-ol-3-one in 1.9 l. of methanol. Add 11.7 g. of sodium borohydride dissolved in 470 m1. of water while stirring the reaction mixture and maintaining the reaction temperature below C; After the addition is complete, stir ,the reaction mixture for 45 minutes at about 5 C.; then cautiously add about 1 1. of 50% aqueous acetone. Boil .the mixture until the temperature reaches 94 C. Cool to 15 C. and filter the resultant precipitate containing 17a-methyl-1,S-androstadiene-Bfl,17fl-diol and the 3.... epimer thereof. Crystallize from methanol to obtain 17a- .methyl-1,5-androstadiene-3/5',17p-diol. Evaporate the methanol filtrate to a residue substantially of 17a-methyl-1,5- androstadiene-Im,17/3-diol. Purifyby chromatography on Florisil eluting with methylene chloride containing increasing amounts of acetone. 1

(C) Alternatively, the compound of this example is prepared as follows. To a solution of methyl magnesium iodide (prepared from 1.50 g. of magnesium and 3.77 ml. of methyl iodide) in 50 ml. of ether, there is added with stirring under an atmosphere of nitrogen a solution of 500 mg. of 1,5-androstadiene-3B-ol-17-one in 25 ml. of tetrahydrofuran. 75 ml. more of tetrahydrofuran is added and the mixture distilled until the vapor temperature reaches ,60" C. The. mixture is then refluxed for one hour, cooled and poured into cold 10%"aqueous ammonium sulfate solution. A solid separates which is filtered, washed with water, dried and crystallized from methanol to give 17amethyl-1,5-androstadiene-3fi,17B-diol.

In a similar manner, 1,5-androstadiene-3a-ol-17-one is reacted with methyl magnesium iodide in ether and there is obtained 17a-methyl-1,5-androstadiene-3u,17/3-diol.

Similarly, by substituting ethyl bromide for methyl iodide in the above procedure there is obtained the corresponding 17a-ethyl derivatives, i.e., 17ot-ethyl-1,5-androstadiene-3[3,17,l3-diol and 17a-ethy1-1 ,5-androstadiene- 3a,17,B-diol, respectively.

. 1.0 EXAMPLE 3 3p-175-diol in 10 ml. of pyridine and 5 ml. of acetic anhydride. Allow the solution to stand at 25 C. for 18 hours; then add 1 ml. of water and pour the reaction mixture into ice cold aqueous hydrochloric acid. Extract the aqueous mixture with methylene chloride. Wash the com- .bined extracts to neutrality with water, dry over magnesium sulfate, filter and evaporate to a residue of 17amethyl-1,5-androstadiene-3,B-17fl-dio1 3-acetate. Purify by crystallization from aqueous methanol.

In a similar manner, treat 17a-methyl-1,5-androstadiene- 3a,17B-diol with acetic anhydride in pyridine and isolate as described above to give 17a-methyl-1,5-androstadiene- 3a,l7/8-diol 3-acetate.

(B) 17a-methyl-1,5-andr0stadiene-3fl,l7/3-di0l dipropionate and 17a-m'ethyl-1,5-androstadiene-3BJ7 3-di0l 3- pr0pi0nate.-Heat a solution of 4 g. of 17a-methyl-1-,5-

androstadiene-3 3,17fl-diol in ml. of pyridine and 40 ml. of propionic anhydride at C. for 23 hours. Add 10 ml. of water and pour the reaction mixture into a solution of 80 ml. of concentrated hydrochloric acid in ice water. Extract the reaction mixture .with methylene ,chloride. Wash the combined extracts to neutrality with ,water, dry over magnesium sulfate, filter, and evaporate to a residue. Chromatograph this residue on 45 g. of 200 mesh of silica gel, eluting with hexane containing increasing quantities of ether. The material eluted with ether-hexane (1:9) is 17a-methyl-1,5-androstadiene-3B,

17B-diol dipropionate; the material eluted with ether-hexane (2:8) is 17a-methyl-1,5-androstadiene-3 3,l7 3-diol 3-propionate. Purify both the monoand di-esters by crystallization from methanol.

In a similar manner, by substituting 17a-methyl-1,5-

,androstadiene-3a, 17 fl-diol for 17a-methyl-1,5-androstadiene'-3 3,17B-diol in the above procedure, there is obtained 17u-methyl-1,S-androstadiene 3a,17,8 diol dipropionate and 17u-methyl-1,5-androstadiene-3 a,17,B-diol 3-propiohydroxide in 10 ml. of water. Stir the reaction mixture at room temperature for an additional hour; then bring to neutrality with acetic acid. Evaporate the reaction mixture in vacuo to a small volume. Dissolve the residue in methylene chloride and wash the methylene chloride solution with aqueous sodium bicarbonate, then water. Dry over magnesium sulfate, filter, and evaporate to a residue of 17a-rnethyl-1,5-androstadiene-3fl,17/3-diol 17- propionate. Purify by crystallization from methanol.

In a similar manner, by substituting 17m-methyl-1,5- andrOstadiene-Su,17,3-diol dipropionate for 17a-methy1-1, S-androstadiene-ZSB,17fi-diol dipropionate in the above procedure there is obtained Hot-methyl-1,5-androstadiene- 3u,17;8-diol 17-propionate.

(D) 17a-methyl-I,5-androstadiene-35J7B-di0l dibenzoate and 17zx-metlzyI-LS-androstadiene-3BJ7/3-a'i0l 3-benzoate.--To a solution of 1 g. of 17a-methy1-1,5-androstadiene-3B,17B-diol in 20 ml. of pyridine cooled to 10 0., add with stirring 2.5 ml. of benzoyl chloride. Stir the reaction mixture at room temperature for 16 hours; then pour into water. Make slightly acid with concentrated hydrochloric acid; then extract with methylene chlonide. Combine the methylene chloride extracts, wash to neutral ity with water, dry over magnesium sulfate, filter, and evaporate to a residue. Chromatograph this residue on 50 g. of 100-20 0 mesh silica gel, eluting with hexane containing increasing amounts of ether. The material eluted with ether-hexane (1:9) is 17ot-meth yl-1,5-and'rostadiene- 1 1 35,17p-diol dibenzoate; the material eluted with 100% ether is l7a-meth-yl-1,5-androstadiene-3p,17,B-diol 3-benzoate. Purify both the monobenzoate and the dibenzoate esters by crystallizing from methanol.

In a similar manner, by substituting l7a-mebhyl-L5-androstadiene-3a,17B-dio1 for 17a-methyl-1,5-androstadiene- 3,9,17B-diol in the above procedure, there is obtained 17amethyl-l,5-androstadiene-3a,17B-diol dibenzoate and 17amethyl-1,5-androstadiene-3a,l7B-diol 3-benzoate, respectively.

(E) 17a-methyl-1,5-androstadiene-3BJ7,8-di0l 3-decanate.To a solution of 1 g. of 17a-methyl-1,5-androstadiene-3,8,l7fldiol in ml. of pyridine cooled to 10 C., add with stirring 3 ml. of decanoyl chloride. Stir the reaction mixture at room temperature for 16 hours; then pour into water. Make the aqueous reaction mixture slightly acid with concentrated hydrochloric acid and extract with methylene chloride. Wash the combined methyl- :ne chloride extracts to neutrality with water, dry over nagnesium sulfate, filter, and evaporate to a residue of ;ubstantially 17a-methyl-1,5-androstadiene-3B,l7fi-diol 3- iecanoate. Purify by crystallization from methanol.

In a similar manner, 17a-methyl-1,5-androstadiene-3a, l7 3-diol is reacted with decanoyl chloride in pyridine and zhere is obtained 17a-methyl-1,5-androstadiene-3a,l7 3- liol 3-decanoate.

(F 17a-methyl-1,5-andr0stadiene-3BJ7B-di0l 3-hemivaccinate and the sodium salt thereof.To 1 g. of 17anethyl-1,5-androstadiene-3fi,17fl-diol in 10 ml. of pyriline add 1 g. of succinic anhydride. Heat the mixture )n a steam bath for one hour; then cool and dilute with vater. Filter the resultant solid which separates and wash vith Water and dry, yielding 17a-methyl-1,5-androstadi- :ne-3fl,17/3-diol 3-hemisuccinate.

To a 1 g. of 17a-methyl-1,5-androstadiene-3/3,17,6-diol i-hemisuccinate suspended in 100 ml. of water add 2 ml. )f a 10% aqueous solution of sodium hydroxide. Evapo- 'ate the resultant aqueous solution in vacuo to a residue )f substantially Hot-methyl-1,5-androstadiene-3B,17/3-diol i-so-dium hemisuccinate.

By substituting 17a-methyl-1,5-androstadiene-3a,17,8- liol for 17a-met1hyl-1,5-androstadiene-3fi,17,9-diol in the tbove procedure there is obtained l7a-methyl-L5-androsadiene-3a,l7/3diol 3-hernisuccinate and 17a-methy1-1,5- .ndrostadiene-3a,17B-diol 3-sodium hemisuccinate, respecively.

(G) 17a-methyl-1,S-androstadienedBJ7 3-di0l 3-sulfate rnd the potassium salt filtereofi-Stir for 2 /2 hours at oom temperature a mixture of 10 g. of 17a-methyl-1,5- ndrostadiene-3;8,17/3-diol and 10 g. of pyridine-sulfur tri- |xide complex in 100' ml. of pyridine. Cool the mixture u an ice bath and add rapidly with vigorous stirring 0 ml. of 50% aqueous potassium hydroxide. Stir the aixture two minutes longer; then allow it to cool to oom temperature Without further stirring. Centrifuge the esultant two-phased system at room temperature and ecant the pyridine layer. Wash the aqueous residue with yridine and combine the pyridine washes with the origial pyridine layer. Add ether to the pyridine solution llth stirring until precipitation is complete. Filter the mixture and dry the residue to give substantially 17aiethyl-1,5-androstadiene-3fi,17B-diol 3-potassium sulfate.

Dissolve 1 g. of 17a-methyl-1,5-androstadiene-3/3,17B- iol 3-potassium sulfate in 100 ml. of water and bring the olution to neutrality by adding hydrochloric acid. Filter nd dry the resultant solid of substantially 17a-methyl-1, -androstadiene-3fi,.17/i-diol 3-sulfate.

By substituting 17a-methyl-1,5-androstadiene-3a,17,8- iol for 17a-methyl-1,5-androstadiene-3/3,l7 3-diol in the bove procedure there is obtained 17a-methyl-1,5-androsldl6I16-30t,17fi-dl0l 3-potassium sulfate and 17a-methyl-1, -androstadiene-3a,l7fi-diol 3-sulfate, respectively.

(H) 17a-methyl-1,5-androstadiene-3BJ7,3-di0l 3-ph0shate and the di-soaium salt there0f.--To a solution of g. of 17u-methyl-1,5-androstadiene-3 8,17p-diol in 10 3-phosphate.

To 1 g. of 17a-methyl-1,5-androstadiene-3B,17fi-diol 3- phosphate suspended in 100 ml. of water, add with stirring 2.2 ml. of a 10% aqueous solution of sodium hydroxide. Evaporate the resultant solution in vacuo to a residue substantially of 17a-methyl-1,5-androstadiene-3fi,l7fi-diol 3-di-sodium phosphate.

By substituting 17a -methyl-1,5-androstadiene-3a,17/3- diol for 17a-methyl-1,5-androstadiene-3BJ7B-diol in the above procedure there is obtained 17u-methyl-L5-androstadiene-3a,17/3-dio1 3-phosphate and 17a.-methy1-1,5-andr-ostadiene-3a,17fi-diol 3-di-sodium phosphate, respective- 1y.

(I) 17a methyl 1,5 androsmdiene 3,8,17fi dial 3- (3'-cycl0pentyl pr0pi0nate).Treat 17a methyl-|1,5-and-rostadiene-3fi,l7,B-diol with w-cyclopentyl propionic acid anhydride in pyridine in a manner similar to that described in Example 3(A). Isolate the resultant product in the described manner to give 17a-methyl-1,S-androstadiene-Sfl, 17fi-diol 3-( 3'-cyclopentyl propionate) By substituting 17a-methyl-l,5-adrostadiene-3a,17/8-di0l for 17a-methy-l-1,5-androstadiene-3fi, 17fi-diol in the above procedure there is obtained 17a-methyl-1,5-androstadiene- 3a,17fl-diol 3 (3-cyclopentyl propionate) EXAMPLE 4 1 ,5 -andr0staa'i ene-3,1 7 ,B-diol (A) 1,5-androstadiene-17B-ol-3-one.--Add 7 ml. of an approximately 18% suspension of sodium acetylide in xylene to a solution of 0.8 g. of 1,4-androstadiene-1718-01-3- one in 16 ml. of dimethylsulfoxide. Stir the reaction mixture under an atmosphere of nitrogen for 50 minutes, then pour cautiously into ice water. Extract the aqueous mixture with ethyl acetate, then combine the extracts and evaporate to a residue of substantially 1,5-androstadiene- 17,8-01-3-one. Purify by chromatography over 20' g. of Florisil eluting with ether-hexane. Combine like fractions which by ultra-violet evalution contain the 3-keto-1,5-diene system and evaporate to a residue. Crystallize the residue from acetone-hexane.

(B) 1,5-andr0stadiene3,17,6-di0l.-1,5 androstadiene- 17B-ol-3-one is reduced with lithium aluminum hydride in tetrahydrofuran in a manner similar to that described in Example 1(B). The resultant mixture of 311- and BB-hydroxy-l,5-androstadiene l7 8-ol is separated by chromatography on Florisil eluting with methylene chloride containing increasing amounts of acetone.

(C) Alternatively, the compound of this example is prepared in the following manner. Hydrolyze the 17-ethylene glycol ketal of 1,5-androstadiene-3,17-dione with aqueous methanol to which a small amount of dilute sulfuric acid has been added in the manner described in Example 1(C). Isolate the resultant product in the described manner to give 1,5-androstadiene-3,17-dione.

Reduce 1,5-androstadiene-3,17-dione with lithium aluminum hydride in tetraydrofuran according to the manner described in Example 1. Isolate and separate the resultant isomeric mixture in the described manner to yield 1,5-ar1- drostadiene 313,176 diol and 1,5-androstadiene-3a,175- diol, respectively.

EXAMPLE 5 1,5-andr0stadiene-3/3J 7 fl-diol 17-acetate (A) 1,5-andr0staaiene-3BJ7,8-diol diacetate.Heat a solution of 4 g. of 1,5-androstadiene-3fl,-l7 8-diol in ml. of pyridine and 40 ml. of acetic anhydride at C 13 for 23 hours. Add 10 ml. of water and pour the reaction mixture into a solution of 80 ml. of concentrated hydrochloric acid in ice water. Extract the reaction mixture with methylene chloride, wash the combined extracts to neutrality with water, dry over magnesium sulfate, filter and evaporate to a residue of substantially 1,5-androstadiene- 313,17/3-diol diacetate. Purify by crystallization from methanol.

In a similar manner, treat 1,5-androstad-iene-3a,17l9-diol with acetic anhydride in pyridine in the above manner to obtain 1,5-androstadiene-3a;17p-diol diacetate.

(B) 1,5 -andrstadiene-3/3,1 7,8-diol 17-acetate.---In a manner similar to that described in Example 3 (C), except the reaction mixture is kept at C. instead of at room temperature, treat 1,5-androstadiene-3B,17fi-diol diacetate with methanolic sodium hydroxide. Isolate the resultant product in the described manner to obtain 1,5-androstadiene-3,9,-17fi-diol-17-acetate. Purify by crystallization from methanol.

Similarly 1,5 androstadiene-3a,17fi-diol diacetate is treated with methanolic sodium hydroxide in the above manner to obtain 1,5-androstadiene-3a,17fi-diol 17-acetate.

EXAMPLE 6 1 7a-ethiny l-] ,5 -androstadiene-3,1 7 p-diol Centrifuge 4 ml. of a 17% suspension of sodium acetylide in xylene and decant the supernatant liquid with 5 ml. of dimethylsulfoxide. Add the sodium acetylide indimethylsulfoxi-de at room temperature to a solution of 500 mg. of 1,S-androstadiene-Iifi-ol-17-one in 17 ml. of dimethylsulfoxide. Stir the mixture at room temperature for 40 minutes; then add ice water, filter the resultant precipitate of substantially 17a-ethinyl-1,S-androstadiene-Bfl,17fi-diol,

wash with water and dry. Purify by crystallization from acetone-hexane.

In a similar manner, treat 1,5-androstadiene-3a-ol-1'7- one with sodium acetylide in dimethylsulfoxide in the above manner to obtain 17a-ethinyl 1,5-androstadiene-3a, 17;3-diol.

In the above procedure by substituting sodium methyl acetylide for sodium acetylide, there is obtained 17a-methylethiny-l-ll,5-androstadiene-3fi,l7 3-diol and 17a methylethinyl-5-androstadiene-3a,17B-diol.

EXAMPLE 7 17a-chl0r0ethinyl-1,S andrOstadiene-SJ 7 fl-diol To 560 mg. of lithium metal in 50 ml. of anhydrous ether, add dropwise over a period of 30 minutes a solution of 2.5 ml. of methyl iodide and ml. of ether. A1- low the mixture to stand for one hour at room temperature; then cool to 0 C. and add dropwise over a period of 15 minutes a solution of 3.1 ml. of 1,2-"clichloroethylene in ml. of ether. Stir the mixture at room temperature for minutes and then add dropwise over a period of 15 minutes a solution of 1.15 g. of 1,5-androstadiene- 3fl-ol-17-one in 20 ml. of tetrahydrofuran. Stir the reaction mixture at room temperature for 18 hours; then cool to 60 C. and add 5 g. of solid ammonium chloride followed by water. Evaporate the ether and filter the resultantaqueous suspension. The residue on the filter comprising 17a-chloroethinyl-1,5-androstadiene-3/3,17B-diol is washed with water and dried. Purify by chromatography on Florisil. Elute with hexane-ether (9:1), concentrate the eluate s, and crystallize the residue from acetonehexane.

By substituting 1,2-dibromoethylene for 1,2-dichloroethylene in the above procedure there is obtained 17abromoethinyl-1,5-androstadiene-3/3,17B-diol.

In a similar manner, 1,5-androstadiene-3a-ol-17-one when treated with lithium chloroacetylide and lithium bromoacetylide in the above-described procedure, there is obtained 17a-chloroethiny1-1,5-androstadiene-3u,17 8- diol and 17a-bromoethinyl-1,5-androstadiene-3a,17B-diol.

14 EXAMPLE 8 9a-hal0gen01,5-androstadiene-3J Ifl-diol-I 7 -one (A) 9a-flu0r0 17 ethylenedioxy 1,4-andr0stadiene- 11/3-0l-3-0ne.Refiux a solution of 1 g. of 9a-fluoro-1,4- androstadiene-l1fl-ol-3,17-dione in ml. of anhydrous benzene and 0.23 ml. of ethylene glycol under -a Dean- Stark separator for 4 hours in the presence of 10 mg. of p-toluenesulfonic acid. Cool the mixture and make slightly basic by the addition of aqueous 10% sodium hydroxide. Separate the organic layer, wash to neutrality with water, and concentrate in vacuo to a residue comprising 9afiuoro 17-ethylenedioxy-1,4-androstadiene-11/3-ol-3-one. Purify by chromatography on Florisil, combine the eluates of hexane and up to 5% ether-hexane, and concentrate the combined eluates.

(B) 90: fluoro 17 ethyIenediaxy-I,5-androstadiene- 11fl-0l-3-0ne.ln a manner similar to that described in Example 1(A), treat 90: fluoro 17 ethylenedioxy-1,4- androstadiene-l1B-ol-3-one with sodium acetylide in dimethylsulfoxide and isolate the resultant product in the described manner to give 9a-fluoro-17-ethylenedioxy-1,5- androstadiene-l1fi-ol-3-one.

(C) 904 fluoro 17 ethylenedioxy-I,S-androstadiene- 3,11B-di0l.Reflux for about two hours a solution of 1 g. of 9u-fluoro-17-ethylenedioxy-1,5-androstadiene-1113-01-3- one and 2g. of purifiedaluminum isopropoxide in 50 ml. of dry isopropanol, at the same time slowly removing by distillation any acetone which is formed. Reflux until the test for acetone in the distillate (2,4-dinitrophenolhydrazone) is negative; then distill the excess isopropanol in vacuo. To the resultant residue add 15 ml. of a concentrated aqueous solution of sodium potassium tartrate. Remove by filtration the resultant precipitate comprising 9a fluoro 17 ethylenedioxy-1,5-androstadiene-3B,11ediol in admixture with 9a-fiuoro-17-ethylenedioxy-1,5- androstadiene-3a,l1 3-diol. Crystallize from acetone-hexane to obtain 9a-fluoro-17-ethylenedioxy-1,5-androstadiene-3,8,11l9-diol. Concentrate the filtrate to dryness, dissolve the resultant residue in methylene chloride, and chromatograph on Florisil to obtain 9a-fiuoro-17-ethylenedioxy-1,5-androsta'diene-3a,1 1 S-diol.

(D) 90: fluoro-1,5-androstadiene-3JIB-diol-I7-0ne. In a manner similar to that described in Example 1(C) treat each of 9u-fiuoro-17-ethylenedioxy-1,S-androstadiene-3;8,ll{3-diol and 9a fluoro 17 ethylenedioxy-1,5- androstadiene-3a,1IB-diol with aqueous sulfuric acid in methanol and isolate the resultant product as described to obtain, respectively, 9ot-fluoro 1,5 androstadiene-3fl, 11,8-diol-17-one and 9a-fluoro-1,5-androstadiene-3u,11B- diol-17-one.

Similarly, 9a-bromo 1,4 androstadiene-lIdol-3,17- dione may be subjected to the sequence of reactions outlined above, i.e., treat with ethylene glycol in the manner of Example 8(A) to obtain 9a-bromo-17-ethylenedioxy- 1,4-androstadiene 115 ol-3-one, which upon treatment with sodium acetylide in 'dimethylsulfoxide in the manner EXAMPLE 9 9a-hal0geno-1 7ot-ethinyl-1,5-androstadiene-3,I7B-di0ls (A) bromo 17a ethiny l-l,S-andfostadiene-IIB, 17,8-di0l-3-0ne.In a manner similar to that described in Example 2(A), 9a-bromo-17a-ethinyl-l,4-androstadiene- 115,17B-dio1-3-0ne is reacted with sodium .acetylide in 15 dimethylsulfoxide. Isolate the resultant product in the described manner to obtain 9a-bromo-17a-ethinyl-l,5-androstadiene-l16,17,8-diol-3-one.

Similarly,

9ct-fiuoro-17m-ethnyl-1,4-androstadiene-l 15,1713- diol-3-one,

9u-chloro-17a-ethinyl-1,4-androstadiene-115,175-

diol-3-one,

9a-fluoro-17a-ethinyl-1,4-androstadiene-l7fi-ol-3,l 1-

dione, and

9a-bromo-17a-ethinyl-1,4-androstadiene-17fl-ol-3,1 1-

dione are each reacted with sodium acetylide in dimethylsulfxide and the resultant products isolated in the described nanner to obtain, respectively,

a-fiuoro-17u-ethinyl-1,5-androstadiene-115,1713- diol-3-one,

)u-chloro-17a-ethinyl-1,5-androstadiene-11,8,17/8- diol-3-one,

)a-fluoro-17a-ethinyl- 1,5-androstadiene-175-01- 3,11-dione, and

)a-bromo-l7a-ethinyl-1,5-androstadiene-l76-01- 3, l l-dione.

(B) 90: bromo 17cc ethinyl 1,5-andrstadienef,11B,17[3-tri0l.ln a manner similar to that described n Example 2(B), treat 9a-bromo-l7a-ethinyl-1,5-androsadiene-l1,8,l7B-diol-3-one with sodium borohydride. Isoate the resultant product containing the 30:- and 3B-hylroxy epimers of 9a-bromo-l7u-ethinyl-1,5-androstadiene- ,11,6,17fl-triol and separate the 30cand 3,6-epimers in he described manner to obtain 9a-bromo-l7ot-ethinyl-1,5- vndrostadiene-Zi/il1,8,17,8-triol and 9u-bromo-l7ot-ethinyl- ,5-androstadiene-3a,1 1,8,17,8-triol.

Similarly,

tat-fluoro-17m-ethinyl-1,5-androstadiene-11,6,17,8-

diol-3-one,

*a-chloro-l7a-ethinyl-1,S-androstadiene-l 1 6-1718- diol-3-one,

ot-fiuoro-l7u-ethinyl-1,S-androstadiene-17 8-01- 3,11-dione, and

u-bromo-l7a-ethinyl-1,5-androstadiene-17fi-ol- 3,1 l-dione re each reacted with sodium borohydride in the aboveescribed manner and the resulting 3aand 3,6-hydroxy pimers separated in the described manner to obtain, repectively,

16-methyl-1,5-andmstadiene-3-0ls (A) 15 3 methyl 17 ethylenedioxy 1,4-andr0srdiene 3,11 di0ne.Treat 16fl-methyl-L4-androstalene-3,1 1,17-trione with ethylene glycol in a manner simir to that described in Example 8(A). Isolate and purify 1e resultant product in the described manner to obtain /8 methyl 17 ethylenedioxy-l,4-androstadiene-3,11- one.

(B) 16/8 methyl-I7-ethylenedioxy-I,5-andr0stadiene- 11-dione.In a manner similar to that described in Ex- 16 ample 2(A), treat 16,8 methyl 17 ethylenedioxy-1,4- androstadiene-3,ll-dione with sodium acetylide in dimethylsulfoxide. Isolate and purify the resultant product in the described manner to obtain 16,8-methyl-l7-ethylenedioxy-1,5-androstadiene-3,1l-dione.

(C) 166 methyl-17-et/zylenedi0xy-1,S-androstadiene- 3-0I-1]-0ne.Cool to 2 C. a solution of 23.4 g. of 165- methyl-17-ethylenedioxy-l,5-androstadiene-3,1l-dione in 1.9 l. of methanol. Add 11.7 g. of sodium borohydride dissolved in 470 ml. of water while stirring the reaction mixture and maintaining the reaction temperature below 15 C. After the addition is complete, stir the reaction mixture for 45 minutes at about 5 C.; then cautiously add about 1 l. of 50% aqueous acetone. Boil the mixture until the mixture temperature reaches 94 C. Cool to 15 C. and filter the resultant precipitate comprising 16,8- methyl 17-ethylenedioxy-1,5-androstadiene-3/8-ol-ll-one and the 3ot-epi1ner thereof, i.e., 16,8-methyl-17-ethylenedioxy-1,5-androstadiene-3ot-ol-l1one. The epimeric mixture is used without further purification in the following procedure 10(D).

(D) 166 methyl-1,5-androstadiene-3-0l-11,17-di0'ne.- Dissolve 1 g. of 16fl-methyl-l7-ethylenedioxy-1,5-androstadiene-3(u and B)-ol-1l-one (prepared as described in Example 10(C) in 10 ml. of aqueous methanol (10 ml. methanol/l ml. water). Add 1 ml. of 10% aqueous sulfuric acid and allow the mixture to stand at room temperature for 6 hours. Add water; then filter the resultant precipitate comprising 16B-methyl-1,5-androstadiene-3flol-11,17-dione and the 3a-epimer thereof. Crystallize from aqueous methanol to obtain as precipitate l6/3-methyl-l,5- androstadiene-318-ol-11,17-dione.

Evaporate the aqueous methanol filtrate in vacuo to a residue comprising 165 -methyl-1,5-androstadiene-3a-ol- 11,17-dione. Purify by dissolving in methylene chloride and chromatograph on Florisil eluting with methylene chloride with increasing amounts of acetone.

In a similar manner, 9ot-brorno-16a-methyl-1,4-androstadiene-l1B-ol-3,17-dione, treated as described in procedures 10(A) through 10(D), is converted to 9a-bromo- 16u-methyl-1,5-androstadiene-3fl,11,6-diol-17-one and the 3ot-epimer thereof, i.e., treat 9oc-b1OInO-l6rx-Inethyl-L4- androstadiene-l lfi-ol-3,l7-dione with ethylene glycol as in Example 10(A) to obtain 9a-bromo-16a-methyl-17-ethylenedioxy-l,4-androstadiene-11fl-ol-3-one which, in turn, is reacted with sodium acetylide in dimethylsulfoxide as described in Example 10(B) to obtain t-b1'O1'1lO-160L- methyl 17-ethylenedioxy-1,5-androstadiene-11B-ol-3-one. Treat the resultant 3-keto-1,5-androstadiene with sodium borohydride according to the procedure of Example 10( C) to obtain the epimeric mixture of 9a-bromo-l6u-methyl- 17-ethylenedi0xy-l,5-androstadiene-3/8,1lfi-diol and the 3a-epimer thereof. Hydrolysis with methanolic-sulfuric acid as described in Example 10(D) yields the epimeric mixture of 9a-bromo-16u-methyl-1,5-a11drostadiene-3(a and B),11,6-diol-17-one, separable by crystallization and chromatographic techniques in the described manner into 90; bromo-16ot-rnethyl-1,5-androstadiene-3fl,11/3-diol-17- one and 9tx-bromo-l6a-metliyl-1,5-androstadiene-3a,11 8- diol-17-one, respectively.

(E) Treat each of 9a-fiuoro-l6B-methyI-L4-androstadiene-1l/3,17B-diol-3-one and 9a-chloro-l6a-methyl-L4-androstadiene-17fi-ol-3,1l-dione with sodium acetylide in dimethylsulfoxide in the manner described in Example 10(B) to obtain, respectively, 9u-fiuo-ro-16fl-methyl-l,5- androstadiene-l1,8,1713-diol-3-0ne and and 9a-chloro-16umethyl-1,5-androstadiene-17,6-01-3,1l-dione.

Treat each of the 3-keto-1,5-androstadienes prepared in the preceding paragraph with sodium borohydride and separate and purify the resultant product in a manner similar to that described in Example 2(B) to obtain, respectively,

9tx-fiuoro-16,8-methyl-1,5-androstadiene- 3,6,1 I B,17 B-triol,

, 17 9a-fluoro-16/3-methyl-1,5-androstadiene-3a,1 1,6,17p-trio1, 9a-chloro-16a-methy1-1,5-androstadiene- 35,176-diol-11-one and 9a-chloro-1 6a-methy1-1,5 -androstadiene- 3 11,17fi-di01-11-011Q.

EXAMPLE 11 (A) 9a,11/3-dichloro 17a methyl-1,5-androstadiene 17p-0l-3-0ne.In a manner similar to that described in Example 1(A), react 911,115-dichloro-17a-methyl-1,4- androstad-iene-l7/8-ol-3-one with sodium acetylide in dimethylsulfoxide and isolate and purify the resultant prodnet in the described manner to give 9a,].1B-dlChlOIO-170tmethyl-1,S-androstadiene-17fl-o1-3-one.

In a similar manner,

are each reacted with sodium acetylide and the resultant products isolated and purified to yield, respectively,

6-fluoro-9u,1 lit-dichloro-17wmethyl-1,5-androstadiene- 1718-ol-3-one,

6,17a-dimethyl-9a, l l e-dichloro-1,5-androstadiene- 1713-01-3 -one, and

(B) 9a,11,8 dichloro-17a methyl 1,5 androstadiene-3,17,B-diol.1n a manner similar to that described in Example 8(C), react 9a,11fl-dichloro17ot-methyl-1,5- androstadiene-17,6-ol-3-one with aluminum isopropoxide in isopropanol, isolate the resultant product, and separate the mixture of 311- and 3B-hydroxy epimers to give 904,11l3- dichloro 17oz methyl-l,5-androstadiene-3,B,17B-diol and 90:,11fl-di0l'1l010 17oz methyl-1,5-androstadiene-3a,17l3 diol, respectively.

Similarly,

6-fiuoro-9u, 1 lfl-dichloro-17a-methyl-1,5-androstadiene- 17 fi-ol-3-one,

6,17a-dimethyl-9u,11,B-dichloro-1,5-androstadiene- 1713-01-3 -one, and

9u-brorno-1 1,B-fluoro-17a-methyl-1,5-androstadiene- 17,8-ol-3-one are each treated with aluminum isopropoxide in isopropanol and the resultant epimeric mixture separated in a manner similar to that described in Example 8(C) to obtain, respectively,

9a,]1/3-dihal0geno-16-alkyl-1,5-androstadiene-3-0ls (A) 9a-brom0-11p-chloro-16a-ethyl-17-ethylenedioxy, 1,4-androstadiene-3-one.-In a manner similar to that described in Example 8 (A), react 9'a-bromo-11B-ch1oro- 16a-ethyl-1,4-androstadiene-3,17-dione with ethylene glycol and isolate-the resultant product as described to give are each treated with aqueous methanol 18 a 9a bromo 11 8 chloro-16a-ethyl-17-ethylenedioxy-1,4- androstadiene-3-one.

Ina similar manner, 9a,1lp-dichloro-l6a-methyl-1,4- androstadiene 3,17 dione and :,11/3 dichloro 16B- methyl-1,4-androstadiene-3,17-dione are each reacted with ethylene glycol and the-re is obtained 9ot,1lfi-diChlOIO-16otmethyl-17-ethylenedioxy-1,4-androstad-iene-3-one and 90:, 11B dichloro 1Gfl-ethyl-17-ethylenedioxy-1,4-androstadiene-3-one.

(B) 9a-br0m 0-11fl-chl0ro-16a-ethyl-17-ethylenedi0xy- 1,5-androstadiene-3-one. ln a manner similar to that described in Example 1(A), react 9a-bromo-11/3-chloro- 16a-ethyl-17-ethylenedioxy-1,4-androstadiene-3-one with sodium acetylide in dimethylsulfoxide and isolate and purify the resultant product to give 9u-bromo-11p-ch1oro- 16a-ethyl-17-ethyleuedioxy-1,5-audrostadiene-3-one.

Similarly, 911,11/3 dichloro 16a-methy1-l7-ethylenedioxy-1,4-androstadiene-3-one and 9u,11fl-dichloro-16,B- methyl-17-ethy1enedioxy-1,4-androstadiene-3-one are each reacted with sodium acetylide in dimethylsulfoxide in the above-described manner and there is obtained, respectively, 90 ,1 1 [3-dichloro-1 6a-methyl- 17 -ethylenedioxy- 1,5

androstadiene-3-one and 911,1lfl-dichloro-l6fl-methyl-17- ethylenedioxy-1,5-androstadiene-3-one.

(C) 9a-br0m0-I1fl-chl0r0-16a-ethyl-17-ethylenedi0xy- I,5 1mdrostadiene-3-o'l.-In a manner similar to that described in Example 8(0), react 9u-bromo-11fl-chloro- 16u-ethyl-17-ethylenedioxy-1,5-androstadiene-3-one with aluminum isopropoxide in isopropanol. Isolate the resultant product and separate into the 311- and 3/3-hydroxy epimers in the manner described to obtain 9a-bromo;11,8- chloro 16oz ethyl 17-ethylenedioxy-1,S-androstadiene- 3B 01 and 9a bromo-llp chloro-16u-ethyl-17-ethylenedioxy-1,5-androstadiene-3a-ol, respectively.

In a similar manner, 904,1lfi-dichloro-l6u-methyl-17- ethylenedioxy 1,5 androstadiene-B-one and 9a,115-dichloro 16/3 methyl-17-ethylenedioxy-1,5-androstadiene- 3-one are each treated with aluminum isopropoxide in 'isopropanol and the resultant productsseparated into 30cand 3p-epimers to obtain, respectively,

911, 1 1,B-dichloro-16a-methyl-17-ethylenedioxy- 1,5-androstadiene-3fi-ol,

904,1 1 8-dich1oro-16u-methyl- 17-ethylenedioxy-1,5-

androstadiene-3 a-ol,

androstadiene-Iafl-ol, and 9u,1 IB-dichloro-16fl-methy1-17-ethylenedioxy- 1,5-androstadiene-3ot-ol.

(D) 90: bromo 1115' chloro 16a ethyl 1,5 -'androstadiene-3-0l-17-0ne.In a manner similar to that described-in Example 1(C), treat 9a-bromo-115-chloro- 16a ethyl 17 ethylenedioxy 1,5 androstadiene 3;?- ol with aqueous methanol and 10% sulfuric acid and isolate the resultant product to give 9a-bromo-11p-chloro- V 16u-ethyl-1,5-androstadiene-3/8-ol-17-one.

In a similar manner,

and 10% sulfuric acid to obtain, respectively,

9a-bromo-1lfl-chloro-lGot-ethyl-1,5-androstadiene-3aol-17-one,

90511fi'dichloro-16u-methyl-1,5-androstadiene-3p-ol- 17-one,

1 9 904,11,8-dichloro-16a-methyl-1,5-androstadiene-3ot-o1- 17-one, 90,1 1 e-dichloro-16fl-methyl-1,5-androstadiene-3 [3-01- 17-one, and 9:1,1 1/3-dichl0ro-l6,8-methyl-1,5-androstadiene-3 oc-Ol- 17-one.

EXAMPLE 13 1 6-methy lene-J ,5 androstadi ene-3 ,1 7 fl-diol hour broth culture of Corynebacterium simplex (A.T.C.C.

6946). The flask is incubated at 28 C. for 24 hours. A second 300 ml. Erlenmeyer flask containing 150 mg. of sterile l6-methylene-4-androstene-17,6-ol-3-one in 5.0 ml. of acetone is inoculated with the 24-hour culture of Corynebacterium simplex (A.T.C.C. 6946). The culturecontaining steroid solution is incubated for 48 hours at 28 to C.

After termination of the transformation period, the pH is 7.2-7.3. The culture is now directly extracted with three equal volumes of chloroform, and the solvent volumes are combined and concentrated on a steam :bath to a residue comprising 16-methylene-1,4-androstadiene-l7 3-ol-3-one, which is purified by crystallization from ether-hexane.

(B) 16 methylene 1,5 androstadiene 17,8 ol 3- 0ne.ln a manner similar to that described in Example 1(A), react 16-methylene-1,4-androstadiene-17fi-ol-3-one with sodium acetylide in dimethylsulfoxide. Isolate and purify the resultant product in the manner described to Jbtain l6-methylene-1,5-androstadiene-17fl-ol-3-one.

(C) 16-methylane-1,5-andr0stadiene-3J7fi-di0L-In a nanner similar to that described in Example 2(B), react l6-methylene-1,S-androstadiene-17,B-ol-3-one With sodium norohydride. In the described manner, isolate the result- 1nt product containing l6-methylene-1,5-androstadiene- 3;3,17,B-dio1 and the 3a-epimer thereof. Crystallize the :pimeric mixture from methanol to obtain a precipitate of l6-methylene-1,5-androstadiene-3fl,17fl-diol.

Evaporate the methanol filtrate to a residue substanially of 16-methylene 1,5 androstadiene 304,175 diol. ?urify by chromatography on Florisil, eluting with methlene chloride containing increasing amounts of acetone.

EXAMPLE 14 3-meth0xy-1,5-andr0stadiene-1 7 -one lrostadiene-17-one. Purify by crystallization from aceone-hexane.

Similarly, treatment of ,5-androstadiene-3a-ol-17-one,

"oi-fluoro-1,5-androstadiene-3,8,11,8-diol-l7-one,

'OL-filIOI'O-1,5-aIldI'OSIadIBIlC-3 a, 1 1 8-di01-17-one,

ix, 1 lfl-dichloro-l 6a-methyl-1,5-ar1drostadiene-3fi-ol- 17-one, and

11,1 1 fl-dichloro-16a-methy1-1,5-androstadiene-3a-ol- 17-one 11th sodium hydride and methyl iodide in the above maner will yield, respectively,

ot-methoxy-l,S-andros'tadiene-l7- one,

fi-methoxy-9a-fluoro-1,5-androstadiene-1 l ,B-ol-17-one,

ot-methoxy-9ot-fiuoro-1,S-androstadiene-l 118-ol-17-one,

fi-methoxy-9a,l 1B-dichloro-l6ot-methyl-l,5-

androstadiene-17-one, and

' 2e 3 a-methoxy-9a,1lfi-dichloro-l6oc-methyl-1,5-

androstadiene-17-one.

EXAMPLE 15 3 -m ethoxy-Z ,5 -andr0stadiene-1 7,8-01

Cool to about 10 C. a solution of 2 g. of 3/3-methoxy- 1,5-androstadiene-17-one in 50 ml. of tetrahydrofuran; then add a solution of 0.75 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran while maintaining the temperature of the reaction mixture below 18 C. After one hour, cautiously add ml. of acetone to destroy any excess lithium aluminum hydride; then add about 1 1. of water and boil the mixture until the temperature reaches 94 C. Cool to 15 C. and filter the resultant solid of 3,8-methoxy-1,5-androstadiene-1713-01. Purify :by crystallization from acetone-hexane.

Similarly, treatment of each of 3a-methoxy-1,S-androstadiene-17-one,

3/3-methoxy-9a-fluoro-1,5-androstadiene-11fi-ol-l7-one,

3ot-methoxy-9ot-fluoro-1,S-androstadiene-l1,8-01-17-0ne,

3 {3-methoxy-9a,1 lfl-dichloro-I6a-methyl-1,5-

androstadiene-17-one, rand 3a-methoxy-9a,11,8-dichloro-16a-methyl-1,5-

androstadiene-17 one with lithium aluminum hydride in tetrahydrofuran in the above manner will yield, respectively,

3 u-methoxy-1,5-androstadiene--01,

3 {3-methoxy-9a-fluoro- 1,5-androstadiene-1 1,8,17B-dio1,

3 a-methoxy-9a-fluoro-1,5-androstadiene-115,17fl-dio1,

3 p-methoxy-9a,1 1fi-dichloro-16a-methyl-1,5-

androstadiene-17/3-ol and 30t-mCthOXy-906,1 1/3-dichloro-l6a-methyl1,5-

androstadiene- 1 75-01.

EXAMPLE 16 3-melh0xy-1 7 a-methy [-1 ,5 -andr0stadiene-1 75-01 (A) In a manner similar to that described in Example 2(C), react 3B-methoxy-1,5-androstadiene-17-one with methyl magnesium iodide. Isolate the resultant product in the described manner to give 3,8-methoxy-17a-methyl- 1,5-androstadiene-17fl-ol. Purify by crystallization from aqueous methanol.

Similarly, treatment of each of 306-I1'16thOXY- 1 ,5-androstadiene-17-one,

3 ,B-methoxy-9ot-fluoro-l,S-androstadiene-I 1,8-ol-l7-one,

3ot-methoxy-9a-fluoro-1,5-andr0stadiene-l 1p-0l-17-one,

3,8-meth0xy-9a,1 1B-dichloro-16a-methyl-1,5-androstadiene-17-one, and

3oc-methoxy-9a,l 1,8-dichloro-16u-methyl-1,S-androstadiene-17-one with methyl magnesium iodide in the above-described manner will yield, respectively,

3 ot-methoxy-17a-methyl-1,5-androstadiene-17fi-ol,

3fi-methoxy-9oc-fluoro-17a-methyl-l,S-androstadiene-1 1 3,

17/3-diol,

3 a-methoxy-9a-fluoro-17a-methyl-1,5-androstadiene-1 15,

17p-diol,

3 fl-methoxy-Q 01,1 1p-dichloro-16a,17a-dimethyl-1,5-androstadiene-17fi-ol, and

3 a-methoxy-9ot,1 lfl-dichloro-l6a,17u-dimethyl-l,5-androstadiene- 175-01.

(B) Alternatively, the compound of this example is prepared in the following manner. Dissolve 1 g. of 17u-methyl-1,5-androstadiene-3,17/3-diol (prepared as described in Example 2(B) without separation of the epimeric mixture (in 10 ml. of methanol to which is added 0.1 ml. of concentrated sulfuric acid. Allow the solution to sand for 3 hours; then neutralize with dilute aqueous sodium carbonate. Evaporate the reaction mixture to a residue containing a mixture of 3fl-methoxy-17a-methyl- 1,5-androstadiene-17fi-ol and the 3ot-epimer thereof. Crystallize the epimeric mixture from methanol to obtain a 21 precipitate of 3B-methoxy-17ut-methy1-1,S-andrOstadiene- 17,8-01.

Evaporate the methanol filtrate to a residue substantially of 3a-methoxy-l7a-methyl-1,5-androstadiene-17fio1. Purify by chromatography on Florisil, eluting with hexane containing increasing amounts of acetone.

EXAMPLE 17 3-methoxy-1 7 m-ethinyl-I ,5 -androstad-iene-1 713-01 In a manner similar to that described in Example 6, react 3fi-methoxy-1,5-androstadiene-17-one with sodium acetylide in dimethylsulfoxide. Isolate the resultant product in the described manner and purify by crystallization from acetone-hexane to yield 3,8-methoxy-17a-ethinyl-1,5- androstadiene-17 {3-01. I

Similarly,

3 a-methoxy-1,5-androstadiene-17-one,

3 B-methoxy-9 a-fluoro-1,5-androstadiene-l l ,8-ol17-one,

3a-methoxy-9ot-fluoro-1,S-androstadiene-I1B-ol-17-one,

3 fi-methoxy-9u-1 1 ,B-dichloro-l 6ot-methyl-1,5 -androstadiene-17-one, and

3 u-methoxy-9 u,1 1,B-dichloro-16a-methyl-1,5-androstadiene-17-one v I are each reacted with sodium acetylide in dimethylsulfoxide in the above-described manner to obtain, respectively,

3 a-methoxy-lh-ethinyl-1,5-androstadiene-17fl-ol,

3/i-methoxy-9a-fluoro-17ot-ethinyl-1,5-androstadiene-11B,

17,8-dio1,

3 a-methoxy-9 u-flllOIO- 17a-ethinyl-1,5-androstadiene-1 1 3,

17 8-diol,

3 ii-methoxy-9 (1,1 lfl-dichloro-16ot-methyl-17a-ethinyl-1,5-

androstadiene-17 13-01, and

3 a-methoxy-9 a,1 l B-dichloro-l 6ot-methyl- 17 ot-ethinyl- 1,5

androstadiene- 175-01.

EXAMPLE 18 9ot-chl0ro-1 6u-methyl-1 ,5 -andrstadienc-3,1 1 fl-dio l-I 7-0ne (A) 9,8,115 epoxy 161x methyl 17 erhylenedioxy- 1,4-andr0stadiene-3-0rie .In a manner similar to that described in Example (A), treat 9fi,11fi-epoxy-16a-meth yl-1,4-androstadiene 3,17-dione with ethylene glycol. Isolate and purifythe resultant product in the described manner to obtain 96,1lfi-epoxy-lGot-methyl-17-ethylenedioxy- 1,4-androstadiene-3-one.

(B) 9fl,11/3-- epoxy 16a methyl 17 ethylenedioxy- 1,5-andr0stadiene-3-one. ln a manner similar to that described in Example 10(B), treat 9B,l1,B-epoxy-16a-methyl-17-ethylenedioxy-1,4-androstadiene-3 one with sodium acetylide in dimethylsulfoxide. Isolate and purify the resultant product in the described manner to obtain 95,115- epoxy 16oz methyl 17 ethylenedioxy 1,5 androstadiene-3-one.

(C) 9 3,115 epoxy 16a mellhyl 17 ethyle nedioxy- 1,5-androstadiene-3-ol.ln a manner similar to that described in Example 10(C), react 9fl,11fi-ep0xy-l6tx-methyl-l7-ethylenedioxy-1,5-androstadiene-3-one with sodium (E) 90: 4 chloro 16d methyl 1,5 midrostadlcne 3,11 8-di0l-17-qne.-Dissolve 1 g. of 90t-ChlOIO-160t-Ineth yl-l7-ethylenedioxy-1,5-androstadiene-3 (a and 3),11p-diol (prepared as described above) in 10 m1. of aqueous methanol (10 ml. methanol/l ml. water). Add 1 ml. of 10%- aqueous sulfuric acid and allow the mixture to stand at room temperature for 6 hours. Add water; then filter the resultant precipitate comprising 9a-chlor0-16a-methyl-l, 5-and-rosta'diene-3BJ1B-diol-17-one and the 3wepirner thereof. crystallize the mixture from aqueous methanol to obtain as precipitate 9tx-chloro-16ot-methyl-1,5aandrostadiene-3[3,11/8-diol-17-one.

Evaporate the aqueous methanol filtrate in vacuo to a residue comprising 9u-chloro-16a-methyl-1,5-androstadiene-3a,11fl-diol-l7-one. Purify by dissolving in methylene chloride and chromatographing on Fl-orisil, eluting with methylene chloride containing increasing amounts of acetone.

EXAMPLE 19 1,5,9 (11 estratriene-3-0l-1 7-0ne Subject 1,4,9(11)-estratriene-3,17-dione to a sequenceof reactions similar to those described in Example 18(A-C), i.e., treat 1,4,9(1l)-estratriene-3,17-dione with ethylene glycol in the manner of Example 18(A) to yield -17-methylenedi0xy-1,4,9(1l)-estratriene-3-one. React the resultant 17-methylenedioxy with sodium acetylide in dimethylsulfoxide as in Example 18(B) to obtain 17-ethyl= enedioxy-l,5,9-(ll)-estratriene-3-one. Reaction with sodium borohydride in the manner of Example 18(C) yields a mixture of 1 7-ethylenedioxy-1,5,9 l l -estratriene-3 13-01- and the 3ot-epimer thereof. Hydrolyze'this epimeric mix ture with aqueous sulfuric acid in the manner of Example 10(D) to obtain a mixture of l,5,9(l1')-estratriene-3B-o1- l7-one and the 3a-epimer thereof. Crystallize the epimeric mixture from aqueous methanol to obtain a precipitate of l,5,9'(ll)-e-stratriene-3B-ol-17-one.

Evaporate the aqueous methanol filtrate invacuo to a residue comprising 1,5,9(l1)-estratriene-3a-ol-l7-one. Purify by dissolving in methylene chloride and chromatographing on Florisil eluting with methylene chloride containing increasing amounts of acetone.

EXAMPLE 20 Esters of 3-metlz0xy-1 ,5 -andr0stadiene-1 7 ,B-ols (A) 3-mthoxy-1,Sgzitdrostadiehe-I7/3-0l 17-acfat e.-'- Heat a solution of 2 g. of 3fi-methoxy-1,5-androstadi ene-l7fl-ol in 40 ml. of pyridine and 20 ml. of acetic 'ari hydride at 85 C. for 16 hours. Add 5 ml. of water and borohydride in water. Isolate the resultant product in the described manner to give a mixture of 9fl,l1B-ep0xy-16etmethyl-l7-ethylenedioxy-1,5-androstadiene-3fi-ol and 95, 11,8 epo'xy 16a methyl 17 ethylenedioxy 1,5 -androstadiene-3a-ol.

(D) 90: chloro 16a methyl 17 ethylenedioxy- 1,5-awdrostadiene-3J1fi-di0l.Saturate a solution of 2.00 mg. of the epimeric mixture of 913,11fl-epoxy-16a-methyl- 17 ethylenedioxy 1,5 androstadiene-3-ol prepare in above Example 18(C) in 10 ml. of an alcohol-free chloroform solution with anhydrous hydrogen. chloride while maintaining a reaction temperature of 0 C.-Allow the solution to stand for 4 hours at 0 C.; then concentrate in vacuo to a residue comprising 9a-chloro-16a-methyl- 17-ethylenedioxy-l,5-androstadiene-3fi,1lfl-diol and 90achloro 16a methyl 17 ethylenedioxy 1,5 androstadiene-3 01,1 1 ,B-diol.

pour the reaction mixture into a solution of 40 ml: of concentrated hydrochloric acid in ice water. Extract the reaction mixture with methylene chloride, wash the combined extracts to neutrality with water, dry over magnesium sulfate, and evaporate to a residue comprising 3B-methoxy-l,5-androstadiene-17fi-ol l7 'acetate. Purify by crystallization from methanol.

(B) In a similar'manner, the following 3-methoxy-1, -5-androstadiene-17 8-ols are reacted with acetic anhydride -in pyridine: .3ot-methoxy-1,5-androstadiene-17fl-ol, 3fl-methoxy-9a-fluoro-1,S-androstadiene-l 1 B, 17 ,B-diol, 3a-methoXy-9ot-fluoro-1,S-androstadiene-11,6,1713-diol,

3 p-methoxy-9ot,l 1,8-dichloro-16ot-methyl-1,5-androstadiene-17fl-ol, 3a-methoxy-9u,1 lp-dichloro-16a-methyl-1,5-androstadiene-17fl-ol, 3/3-methoxy-17u-methyl-1,5-androstadiene-17 8-01, 3a-methoxy-17a-methyl-1,S-androstadiene-l7j6-ol, I 3/3-methoxy-17a-ethinyl-1,5-androstadiene-175-01, and 3a-methoxy-17u-ethinyl-1,5-androstadiene-17 3-01, to obtain the respective 17-acetate esters, ie.,

3tx-methoxy-l,5-androstadiene-17/3-ol 17-acetate, 3;.8-methoxy-9a-fiuoro-1,5-androstadiene-1113,17p-diol 17- acetate,

23 lm-methoxy-9ot-fiuoro-1,5-androstadiene-11,8,17,6-diol 17- acetate, LB-methoxy-9a,1 1 5-dichloro-1 6a-methyl-1 ,S-androstadiene-17fl-ol 17-acetate, lot-methoxy-9u, 11,6-dichloro-16u-methyl-1,5-androstadiene-17,8-ol 17-acetate, /i-methoxy-17a-methyl-1,5-androstadiene-17B-ol 17- acetate, a-methoxy-lh-methyl-1,5-androstadiene-17fi-ol 17- acetate, fl-methoxy-17u-ethinyl-1,5-androstadiene-17,6-01 17- acetate, and ot-methoxy-17a-ethinyl-1,5-androstadiene-17/3-ol 17- acetate.

EXAMPLE 21 1,5-pregnadiene-3,II[3,1 7 a,21 -tetr0 l-20-0ne (A) 17a,20;20,21 bis methylenedioxy-I,5-pregna'dine-3,11-di0ne.Add 1.51 l. of 20% sodium acetylide 1 Xylene to a solution of 37.8 g. of 17a,20;20,2l-biS- lethylenedioxy-1,4-pregnadiene-3,1l-dione in 1.51 l. of imethylformamide. Stir the reaction mixture at room emperature for four hours, then pour into 20 l. of ice water; extract the aqueous solution three times with 2 l. ortions of methylene chloride. Combine the methylene hloride extracts, wash to neutrality with water, dry over iagnesium sulfate, filter, and evaporate to a residue omprising 17oz,2();20,21 bis-methylenedioxy-1,5-pregn-aiene3,ll-dione. Purify by crystallization from acetone.

(B) 17 t,20;20,21-bis-methylenea ioxy-1,5-pregnadiene ,1 1 fi-dioL-To a suspension of 19 g. of lithium aluminum ydride in a mixture of 500 ml. of tetrahydrofuran and 00 ml. of diethyl ether at 0 C. and under a nitrogen tmo'sphere, add dropwise a solution of g. of l7a,20;20, l-bis-methylenedioxy-1,5-pregnadiene- 3,11-dione in 400 ll. of tetrahydrofuran. Stir under a nitrogen atmosphere )r 60 hours at room temperature. Cool the mixture to C. and decompose any remaining lithium aluminum ydride by the dropwise addition of a saturated solution f sodium sulfate. Filter the reaction mixture and dry re organic layer over anhydrous sodium sulfate and Jncentrate in vacuo to a residue comprising 17a,20;20*, l bis-methylenedioxy-l,5-pregnadiene-3fi,1lfl-diol and 1e 3a-epimer thereof. Chromatogr-aph the epimeric lixture on alumina, employing the gradient elution iethods, eluting with benzene containing increasing nounts of ether. Combine the like, early eluates, con- :ntrate to a residue and recrystallize several times from :etone to obtain 17u,2();20,2l-bis-methylenedioxy-l,5- regnadiene-3 Q, 1 1 ,B-diol.

Combine the like, late benzene-chloroform eluate fracons, concentrate to a residue, recrystallize several times, 1d there is obtained 17a,20;20,21-bis-methylenedioxy-1, -pregnadiene-3u,1lfl-diol.

(C) 1,5 pregnadiene 3,11;3,17 x,21-letro l-20-one. llow to stand at C. for 18 hours a solution of 200 g. of 17a,20;20,2l-bis-methylenedioxyl-1,5-pregnadiene- 3,11,8-diol in 20 ml. of 80% aqueous formic acid con- .ining 0.02 ml. of 60% perchloric acid. Pour the re- :tion mixture into water, extract with methylene chlode and wash the combined extracts with dilute alkali 1d then water. Dry the methylene chloride extracts over agnesium sulfate, filter, and concentrate in vacuo to a sidue. Dissolve this residue in 20 ml. of methanol 1d add a solution of 10 mg. of sodium hydroxide in 1 l. of Water. Allow this solution to stand for one hour; .en neutralize with acetic acid and evaporate to a sidue. Add chloroform to the residue, filter, and evapate the chloroform extract to a residue comprising 1, pregnadiene-3fl,11fl,17u,2l-tetrol-20-one. Purify by tri- .ration of the residue with ethyl acetate followed by ystallization of the triturated solid from ethyl acetate. Similarly, 17a,20;20,2l-bis-methylenedioxy-1,5-pregnaene-3a,11B-diol, upon reaction with formic acid and perchloric acid and isolation of the resultant product in the above described manner yields 1,5-pregnadiene-3a, 1 1,8,17a,2 1-tetrol-20-one.

(D) Alternatively, react the epimeric mixture of 17a, 20,20,21 bis methylenedioxy-1,5-pregnadiene-3[3,11(3- diol and the corresponding 3ot-hydroxy compound, prepared as described in Example 21(B), (prior to separation into the respective 3ocand 3 B-hydroxy components) with formic acid and perchloric acid in a manner similar to that described in Example 21(C). Isolate the resultant product in the described manner to obtain a mixture of 1,5-pregnadiene-3,8,11B,17a,21-tetrol-20-one and the 3mepimer thereof. Crystallize the epimeric mixture from methanol to obtain a precipitate of 1,5-pregnadiene-3fi, 11/3,17a,2l-tetrol-20-one.

Concentrate the methanol filtrate to a residue. Dissolve this residue in methylene chloride and chromatograph on Florisil eluting with methylene chloride containing increasing amounts of methanol. Combine like fractions and concentrate the combined fractions to a residue comprising 1,5 pregnadiene-3a,11p,17a,21 tetrol-ZO-one. Purify by crystallization from methanol.

EXAMPLE 22 Derivatives 0 f 1,5-pregnadiene-3,1IB,1 7 04,21 -tetr0l-20-0ne (A) In a manner similar to that described in Example 21 (A), react each of the following compounds with sodium acetylide in dimethylsulfoxide; 9a-fluoro-17a,20;20,2l-bis-methylenedioxy- 1,4-pregnadiene-11;6-ol3-one, 6u-methyl-17a,20;20,2l-bis-methylenedioxy- 1,4-pregnadiene-11,B-ol-3-one, 6u-fluoro-17u,2 0;20,2l-bis-methylenedioxy- 1,4-pregnadiene-1 l5-ol-3-one, 1-6u-methyl-17a,'20;20,2 l-bis-methylenedioxy- 1,4-pregnadiene-11/3-ol-3-one, 16,8-methyl-17a,2'0;20,21bis-methylenedioxy- 1,4-pregnadiene-11/3-ol-3-one, 9ix-fluoro-16a-methyl-17a,20;20,21-bis-methylenedioxy- 1,4-pregnadiene-1 1/3-ol-3-one, 60c-II1GthYl-9u-fill0f0-17u,20l;20',2 l-bis-methylenedioxy- 1,4-pregnadiene-l lfl-ol-3-one, 6a, l6oz-di1'n6thYl-9oc-fll1010-l7ot,2U;20,21-bi$- methylenedioxy-1,4-pregnadiene-1 lfl-ol-B-one, 6a,9a-difluoro-17a,20;2 0,21-bis-methylenedioxy- 1,4-pregnadiene-11,8-ol-3-one, 16-methylene-17a,20;20,2l-bis-methylenedioxy- 1,4-pregnadiene-1 1,8-ol-3-one, and 17a,20;20,21-bis-methylenedioxy-1,4-pregnadiene- 11,8,14u-diol-3-one.

Isolate the respective resultant products in a manner similar to that described to obtain, respectively, 9a fluoro-17a,'20;20,21-bis-methylenedioxy-1,5-

pregnadiene-l 1 6-01-3 -0ne, 6-methyl- 17 a,20;20,2l-bis-methylenedioxy- 1,5-pregnadiene-l1fi-ol-3-one, 6-fluoro-17a,20;2 0',2 l-bis-methylenedioxy- 1,5 pregnadienel 1,8-ol-3-one, 16a-methyl-17u,20;20=,2l-bis-methylenedioxy- 1,5-pregnadiene-1 1,8-ol-3-one, -methyl-1711,20;20,2l-bis-methylenedioxy-1,5-

pregnadiene-l 15-ol-3-one, 9OL-flUOl'O-160L-H1ethy1- 1 7a,20;20,2l-bis-methylenedioxy- 1,5-pregnadiene-11,8-01-3-one, 6-methy1-9a-fluoro-17a,20;20,21-bis-methylenedioxy- 1,5-pregnadiene-l 1fl-ol-3-one, 6,16a-dimethyl-9a-fluoro-17a,20-;20,2 l-bismethylenedioxy-1,5-pregnadiene-1 15-ol-3-one, 6,9a-difluoro-17a,20;20,21-bis-methylenedioxy-1,5-

pregnadiene-l 1B-ol-3 -one, 16-methylene-l7u,20;20,21-bis-methylenedioxy- 1,5 -pregnadiene-1 1 fl-ol-3-one, and 17a,20;20,21 bis-methylenedioxy-1,5-pregnadiene- 11p,14u-diol-3-one.

6,9a-difluoro-17u,20;20,2l-bis-methylenedioxy- 1,5-pregnadiene-3 ,1 lfi-diol, 1 6-methylene-17a,20;20,21-bis-methylenedioxy- 1,5-pregnadiene-3,1 lB-diol, and 17u,20;20,21-bis-methylenedioxy-1,5-pregnadiene- 3 ,1 15,14u-tril, respectively.

(C) In a manner esimilar to that described in Example 21 (D), each 3-hydroxy-1,5-pregnadiene prepared as described in above Example 22(B) is reacted 'with formic acid and perchloric acid and the respective resultant products isolated in the described manner whereby is obtained, respectively,

9a-fiuoro-1,5-pregnadiene-3 a,1 1 B, 17 a,21-t6tIO1-20-OI16, 6-methyl-1,5-pregnadiene-3fl,1 1,8,17a,21-tetr-ol-20-one, 6-methyl-1,5-pregnadiene-3 a, 1 118,1 711,2 l-tetrol-ZO-orie, 6-fluoro- 1 ,5-pregnadiene-3B,1 15,17a,21-tetrol-2 0 onc, 6-fiuoro-1,5-pregnadiene-3a,1 1 e, 1.7 a,2 1-tetrol-20-one, i 16a-methyl-1,5-pregnadiene-3,B,11/3,17u,21-tetrol 20-one, 16u-methyl-1,5-pregnadiene-3 0:,11B,17bt,2l-tetrol-2O-one, l 6B-methyl-1,5-pregnadiene-3,l3,1 1B, 17cc,21-16t1'0l20-0116, 16,8-methy1-1,5-pregnadiene-3 04,115,17a,21 tetrol-20-one, I 9a-fluoro-16oc-methyl-l,5-pregnadiene-3B,l 1p,17d,2-1- tetrol-ZO-one, 9a-fluoro- 1 6a-methyl-1,5-pregnadiene-3 11,1 1,B-17 t,21-

tetrol-20-one, 6-methyl-9a-fiuoro-l,5-pregnadiene-3,B,11fl,17x,21-

tetrol-ZO-bne, =6-methyl-9a-fluoro-1,5-pregnadiene-3 a,l 15, l7a,2 1-

tetrol-ZO-one, 6,16u-dimethyl-9a-fluor-o-1,5-pregnadiene-3fi,1 113,17a,21-

tetrol-ZO-one, I 6,16a-dimethyl-9a-fluor0 1,5pregnadiene-3u,1113,17a,21-

tetrol-2-0-one, 4 6,9a-difluoro-1 ,5-pregnadiene-3;3,1 15, 1700,21-1611101- 20-one, 6,9a-difluoro-1,5-pregnadiene 3 11,1 1fi,17a,21-tetrol- 20-one, 16-methylene-1,5-pregnadiene-3fl,11B,17a,21-tetrol- 2O-one, 16-methylene-1,5-pregnadiene-3 oc,1 1fi,17a,21-tetrol- ZO-one, 1,5-pregnadiene-3B,11 8,16,17a,21-pentol 20-one, and 1,5-pregnadiene-3 11,1113,14a,17d,21-pentol-20-one.

EXAMPLE 23 1 ,5 -pregnadiene-3,1 7a,21-tri0l-11,20-di0nes (A) 17u,20;20,21 bis-methylenedioxy 1,5 pregnadz'ene-3,11-di0nes.-In a manner similar to that described in Example 21(A), react 17a,2-0;20,2l-bis-methylenedioxy-1,4-pregnadiene-3,1l-dione with sodium acetylide in dimethylsulfoxide and isolate and purify the resultant 26 product in the described manner to give 17u,2-0;20,21- bis-methylenedioxy-l ,5-pregnadiene-3,1 l-dione.

In a similar manner,

16a-methyl-17a,20,;20,2 l-bis-methylenedi-oxy-1,4-

pregnadiene-3,11-dione,

16/i-methyl-17a,20;2(),21-bismethylenedioxy-L4- pregnadiene-3,1 l-dione, and

9a-fluoro-17a,20;20,2l-bis-methylenedioxy-1,4-

pregnadiene-3,1 l-dione are each reacted with sodium acetylide in dimethylsulfoxide and the resultant products isolated and purified to give respectively,

160L-II1ethyl170t,20';20,2 1-bis-methylenedioxy-1,5-

pregnadiene-3, 1 l-dione,

1 6/3-methyl-17a,20;2(),2l-bis-methylenedioxy-1,5-

pregnadiene-3,l1-dione, and

Sim-fluoro-17a,20;20,2l-bis-methylenedioxy-1,5-

pregnadiene-B ,1 l-dione.

(B) ]7oc,20,'20,21 bis methylenedioxy 1,5 pregnadiene 3 ol 1] 0nes.Dissolve 1.5 g. of 17a,20;20,21- bis-methylenedioxy-1,5-pregnadiene-3,1l-dione in 120 ml. of methanol and cool to about 10 C. Add a solution of 0.8 g. of sodium borohydride in 30 ml. of water while maintaining the reaction temperature below 18 C. After one hour, cautiously add about 15 ml. of acetone to destroy any excess'sodium borohydride. Add 100 ml. of water to the reaction mixture and boil until the temperature reaches 94 C. Cool to about 15 C. and filter the insoluble fraction comprising a mixture of l7a,2'0;20,21-biS- methylenedioxy-1,5-pregnadiene-3 3-ol-ll-one and 17a, 20;20,21 bis methylenedioxy 1,5 pregnadiene 3aol-ll-one. Use the epimeric mixture without further purification in procedure C below.

Ina similar manner,

16a methyl 17oz, 20,20,21 bis methylenedioxy 1,5-

. pregnadiene-3,1l-dione,

16,8 methyl 17a,20;20,21 bis methylenedioxy 1,5-

pregnadiene-3,1 l-dione, and

9a fiuoro 17a,20;20,21 bis methylenedioxy 1,5-

pregnadiene-BJ 1'-dione are each reacted with sodium borohydride in water and the resultant products isolated as described to obtain, respectively, product mixtures comprising 16a methyl 17oz, 20;20,21 bis methylenedioxy 1,5-

(C) 1-5 pregnadiene-3,17a,21 triol 11,20-dione.-- Allow to stand at 25 C. for 18 hours a solution of he epimeric mixture of 17a,20;20,2l-bis-methylenedioxy- 1,5-pregnadiene-3fl-ol-1l-one and the corresponding 3ahydroxy compound, prepared as described in Example 23 (B), in 20 ml. of aqueous formic acid containing 0.02 ml. of 60% perchl-oric acid. Pour the reaction mixture into water, extract with methylene chloride, and wash the combined extracts with dilute alkali and then water. Dry the methylene chloride extracts .over magnesium sulfate, filter, and concentrate in vacuo to a residue.- Dissolve this residue in 20 ml. of methanol and add a solution of 10 mg. of sodium hydroxide in 1 ml. of water. Allow this solution to stand for one hour; then neutralize with acetic acid and evaporate to a residue comprising a mixture of 1,5-pregnadiene-3B,17,21-triol-11,20-dione and the Bot-epimer thereof. Crystallize the epimeric mixture from methanol to obtain a precipitate of 1,5-pregnadiene-3fl-17a,2l-triol 3,20-dione.

16a methyl 171x, 20-;20,21 bis methylenedioxy 1,5-

pregnadiene-B-ol-l l-one,

16B methyl 1701,20;20,21 bis methylenedioxy 1,5-

pregnadiene-3-ol-11-one, and

Q11 fiuoro 170c,2020,21 bis methylenedioxy 1,5-

pregnadiene-3-ol-1l-one,

prepared as described in Example 23 (B), are each reacted with formic acid and perchloric acid and the resultant products isolated and purified as described above to yield, respectively,

160: methyl 1,5 pregnadiene '3B,171x,21 triol 11,20-

dione,

16a methyl 1,5 pregnadiene 3a,17oc,21 triol 11,20-

dione,

16B methyl 1,5 pregnadiene 3,8,17oc,21 triol 11,20-

dione,

16B methyl 1,5 pregnadiene 31x,17o1,21 triol 11,20-

dione,

lot fiuoro 1,5 pregnadiene 3B,171x,21-triol 11, 20-

di-one, and

la fiuoro 1,5 pregnadiene 31x,l7ot,21 triol 11,20-

dione.

EXAMPLE 24 1x,11B dichloro 1,5 pregnadiene 3,171x,21 triol- 20-0ne (A) 901,11B dichloro 1,5 pregnadiene 1713,21- iiol 3,20 dione 1701,21 acetone-To a solution )f 5.8 g. of 913,11B dichloro 1,4 pregnadiene 1711, 1-diol-3,20-dione 17a,21-acetonide in 120 ml. of anhylrous tetrahydrofuran, add 1.5 g. of sodium amide. Stir he mixture at reflux temperature under a nitrogen atmosnhere overnight; then cool and pour into 800 ml. of a :ool, saturated, aqueous boric acid solution. Separate the arganic layer from the aqueous solution; then extract the iqueous solution With ether. Combine the ether extracts vith the original organic layer and evaporate in vacuo to residue comprising 901,11B-dichloro-1,5-pregnadiene- 71x,21 diol 3,20 dione 17a,21 acetonide. Purify by hromatography on Florisil, eluting With benezene conaining increasing amounts of chloroform.

(B) 91:1,I1B dichloro 1,5 pregnadiene 3,171x,21 rial 20 one 171x, 2] acetonide.-React 901,11B-dihloro 1,5 pregnadiene 1713,21 diol 3,20 dione 7a,21-acetonide with sodium borohydride in water in a ianner similar to that described in Example 23(B). solate the resultant product in the described manner to btain a mixture of 91x,1lB-dichloro-1,5-pregnadiene- B,171x,21-trio1-20-one 17a,21-acetonide and 913,11B-dihloro 1,5 pregnadiene 3a,l7oc,21-tfl0l 20-one 1701,21- cetonide which is used Without further purification in 1e following procedure (C).

(C) 901,11B dichloro 1,5 pregnadiene -3,171x,21 iol 20 ne.-To a solution of 1 g. of the epimeric iixture comprising 91x,l1B dichloro 1,5-pregnadiene- B,17o1,21 triol 2O one 1713,21 acetonide and the u-epimer thereof in 15 ml. of glacial acetic acid at 80 add ml. of water over a ten minute period during 'hich time the temperature is allower to rise to 95 C. ool the reaction mixture and filter the resultant solid )mprising a mixture of 9111,11 B-dichloro-l,5-pregnadiene- 8,171x,21-triol-20-one and the 31x-epilmer thereof. Crystalze the epimeric mixture from methanol and filter the recipitate of 901,1IB-dichloro-3B,171x,2l-one.

Concentrate the methanol filtrate to a residue. Dissolve llS residue in methylene chloride and chromatograph on lorisil, eluting with methylene chloride containing increasing amounts of methanol. Combine like fractions and concentrate to a residue comprising 91x,11B-dichloro-l,5- pregnadiene-3a,171x,21-triol-20-one. Purify by crystallization from methanol.

In a similar manner, each of the following compounds, i.e.,

901-11B-dichloro-161:1-methyl-1,4-pregnadiene-1713,21-di0l- 3,20-dione 171x,21-acetonide, 901-1lB-dichloro-16B-methyl-1,4-pregnadiene-l71x,21-

diol-3,20-dione 171:1,2l-acetonide, 91x-chloro-l,4-pregnadiene-11B,17a,2l-triol-3,20-dione 171:1,2 l-acetonide, 91x-chloro-l61x-methyl-1,4-pregnadiene-l 1B, :,21-f1i0l- 3,20-dione 17a,21-acetonide, and 91x-chloro-16B-methyl-1,4-pregnadiene-1 1B, 171x,21-triol- 3 ,20-dione 171:1,2 1 -acetonide are reacted with sodium amide in the manner of Example 24(A) to obtain the corresponding respective 1,5-pregnadiene analogs, each of which in turn is reacted With sodium borohydride in water in the manner of Example 24(B) whereby is obtained the following respective epimeric mixtures; 911,11B dichloro 161x-methyl-1,5-pregnadiene- 3B,17a,2l-triol-20-one l71x,2l-acetonide and the 31 1-epimer thereof, 901,1lB-dichloro-16B-methyl-1,5-pregnadiene, 3B, 171x,21-triol-20-one 17,21-acetonide and the 31x-epimer thereof, 91x chloro-1,5-pregnadiene-3B,11B,l7o1,21-tetrol- 20-one l71x,2l-acetonide and the 31 1-epimer thereof, 9o1- chloro-161x-methyl 1,5-pregnadiene-3B,11B,l7o1,21-tetrol- 20-one 171x,21-acetonide and the 31x-epimer thereof, and 91x-chloro-16B-methyl 1,5 pregnadiene 3B,11B,171x,21- tetrol-ZO-one 171x,21-acetonide and the 31x-epimer thereof. Hydrolyze each of the foregoing epimeric mixtures with 50% aqueous acetic acid in the manner described in Example 24(C) and the resultant epimeric mixtures are isolated and purified in a manner similar to that described to obtain 901,1lB-dichloro-161x-methyl-1,5-pregnadiene-3B,1701,21-

triol-20-one,

911,1lB-dichloro-16o1-methyl-1,5-pregnadiene-3 0c,170c,21-

triol-20-one,

901,11B-dichlor-o-l6B-methyl-1,5-pregnadiene-3B,1701,21-

triol-20-one,

901,1lB-dichloro-l6B-methyl-1,5-pregnadiene-3 o1,l71 1,21-

triol-20-one,

9a-chloro, 1,5-pregnadiene-3 B, 1 1B, 1 711,2 1 -tetrol-20-one,

9a-Chl01'0- 1 ,5-pregnadiene-3 11-11B,171 1,2l-tetrol-20-one,

9o1-chloro161x-methyl-1,5-pregnadiene-3B, 1 1B, 1701,21-

tetrol-20-one,

91x-chloro-l 61x-methy1-1,5-pregnadiene-3 oc,11/3,171x,21-

tetrol-20-one,

91x-chloro-l6B-methyl-1,5-pregnadiene-3B, 1 1B, 1701,21-

tetrol-20-one, and

9nc-Chl01'0- l 6B-methyl- 1,5-pregnadiene-3 01,1 1 B, 1 711,2 1-

tetrol-20-one.

EXAMPLE 25 1,5-pregnadiene-3,I71x-a'i0Z-20-0ne (A) 20 ethy-lenedioxyl 1,4 pregnadiene 1701-01-3- one.Treat 1,4-pregnadiene-171x-ol-3,20-dione with ethylene glycol in the presence of p-toluenesulfonic acid in a manner similar to that described in Example 8(A); isolate and purify the resultant product in a manner similar to that described to obtain 20-ethylenedioxy-1,4-pregnadiene- 171x-ol-3-one.

(B) 20 ethylenedioxy 1,5-pregnadiene-171x-ol-one.- React 20-ethylenedioxy-1,4-pregnadiene-l71x-ol-3-one with sodium acetylide in dimethylsulfoxide and isolate and purify the resultant product in a manner similar to that described in Example 1(A) to obtain 20-ethylenedioxy- 1,S-pregnadiene-l71x-ol-3-one.

(C) 20 ethylenedioxy-J,5-pregnadiene-3,17o1-di0l.In a manner similar to that described in Example 23 (B), treat 20-ethylenedioxy-1,5-pregnadiene-171x-ol-3-0ne with sodium borohydride in water and isolate the resultant 29 product comprising a mixture of 20-ethylenedioxy-1,5- pregnadiene-3l3,17a-diol and 20-ethylenedioxy-1,S-pregnadiene-3 u, 17OL-dl01.

(D) 1,5-pregnadiene-3,17a-diol-20-one.--Dissolve 5 g. of the epimeric mixture of ZO-ethylene-dioxy-1,5-pregnadiene-3,17a-diol in ml. of aqueous methanol (10 ml. methanol/1 ml. water). Add 1 ml. of 10% aqueous sulfuric acid and allow the mixture to stand at room temperature for 6 hours. Add water; then filter the resultant precipitate comprising a mixture of 1,5-pregnadiene-3B,17mdiol--one and the Got-epimer thereof. Crystallize the epimeric mixture from aqueous methanol and filter the resultant precipitate of 1,5-pregnadiene-3fi,17a-diol-20- one.

Evaporate the methanol filtrate to a residue. Chromatograph the residue on Florisil, eluting with methylene chloride containing increasing amounts of acetone. Combine like fractions and evaporate in vacuo to a residue of substantially 1,5-pregnadiene-3u,17a-diol-20-one. Purify by crystallization from methanol.

In a manner similar to that described above, 9oz-11B- dichloro-1,4-pregnadiene-3,20-dione, 21-fluoro-1,4-pregnadi8ne-17a-0l-3,20-di0n8, 1,4- pregnadiene-3,20-dione, 6amethyl-1,4-pregnadiene-3,20-dione, 60c fluoro-1,4-pregna diene-3,20-dione, and 16ot-methyl 1,4 pregnadiene-3,20- dione are each converted to their respective ZO-ethylene glycol ketal by reaction with ehylene glycol in a manner similar to that described in Example (A), each of which in turn is reacted with sodium acetylide in dimethylsulfoxide in the manner of Example 25(B) to obtain, respectively,

9 u,11B-dichloro-20-ethylenedioxy-1,5-pregnadiene 3-one, ZO-ethyIenedioXy-Zl-fluoro-1,S-pregnadiene-17a-ol-3-one, ZO-ethylenedioxy-l ,5-pregnadiene-3-one, 6-methyl-20-ethylenedioxy, 1,5 -pregnadiene-3 -one, 6-fluoro-20-ethylenedioxy-1,5-pregnadiene-3-one, and 16a-methyl-ZO-ethylenedioxy-1,5-pregnadiene-3-one.

9a,1lB-dichloro-l,5-pregnadiene-3 ,B-ol-20-one, 90,11/8-dichloro-1,5-pregnadiene-3a-ol-20-one, 21-fiu0r0-1,5-pregnadiene-3B,l7a-di0l-20-0ne, 21-fluoro-1,5-pregnadiene-3 0t,17oc-di0l-20-0I16, 1,5-pregnadiene-3fl-ol-20-one,

1,5 -pregnadiene-3 oc0l-20-One, 6-methyl-1,5-pregnadiene-3 B-ol-20-one, 6-methyl- 1,5 -pregnadiene-3 a-ol-20-one, 6-fluoro-1,5-pregnadiene-3fl-ol-ZO-one, 6-fiuoro-1,5-pregnadiene-3 a-ol-20-one, 16a-methyl-1,5-pregnadiene-3B-ol-ZO-one, and 1Got-methyl-l,5-pregnadiene-3a-ol-ZO-one.

EXAMPLE 26 9a,]IB-dichloro-I,5-pregnadiene-3J7u-di0l-20-0ne 1 7 -acetate (A) 9a,]1fi-dichZora-1,5-pregnadiene-17ot-ol-3,20-dione 17-acetate.-In a manner similar to that described in Example 23(A), react 911,1lpdichloro-1,4-pregnadiene- 17a-ol-3,20-dione 17-acetate with sodium acetylide in dimethylsulfoxide. Isolate and purify the resultant product in a manner similar to that described to give ,11B-dlchloro-1,5-pregnadiene-17a-ol-3,20-dione 17-acetate.

[n a similar manner, 1,4-pregnadiene-17a-ol-3,20-dione 17-acetate and 9a-fluoro-1,4-pregnadiene-11,3,l7ot-di0l-3, ZO-dione 17-acetate are each reacted with sodium acetylide in dimethylsulfoxide whereby is obtained 1,5-pregnadiene- 17a-ol-3,20-dione 17-acetate and 9a-fluoro-1,5-pregnadiene-l 1B, 17a-diol-3,20-dione 17-acetate.

(B) 9a,]15-dichlor0-1 ,5-pregnadiene-3J 7a-diol-20-0ne I7-acetate.In a manner similar to that described in Example 23(B), react 9oc,1lfl-dichloro-1,5-pregnadiene- 17u-0l-3,20di0116 17-acetate with sodium borohydride in water. Isolate the resultant product in the manner described to obtain a mixture comprising 9a,11[3-dichloro- 1,5-pregnadiene-3 [3,17m-diol-20-0ne 17-acetate and the 31xepimer thereof. Crystallize the epimeric mixture from aqueous methanol to obtain a precipitate of 9a,11;8 lichloro-1,5-pregnadiene-3B,17a-diol-20-one 17-acetate.

Evaporate the methanol filtrate in vacuo to a residue comprising 90,11fi diCl'llOIO-1,5-p16g1'1fidl6116-3a,17ot-dl0l- 20-one 17-acetate. Purify by chromatography on Florisil, eluting with methylene chloride containing increasing amounts of methanol. Combine like fractions and concentrate the combined fractions to a residue comprising 9a, dichloro-1,5-pregnadiene-3u,17a-diol-20-one 17-acetate.

In a similar manner, reaction of 1,5-pregnadiene-17aol-3,20-dione 17-acetate and 9rx-fluoro-1,5-pregnadiene- 11fl,17a-diol-3,20-dione 17-acetate with sodium borohydride in Water and isolation and purification of the resultant product in the above-described manner will yield 1,5-pregnadiene-3B,17a diol-20-one 17-acetate, 1,5-pregnadiene-3a,17a-diol20-one 17-acetate, 9a-fluoro-1,5-pregnadiene-3B,l1B,17u-triol-20-one 17-acetate and 9a-fiuoro-1,5- pregnadiene-3a,11fl,17a-triol-20-one 17-acetate, respectively.

EXAMPLE 27 3-meth0xy-1 ,5 -pregnadiene-1 1 {3,1 7 0:,21 -triol-20-0ne (A) 3 meth0xy-17a,20;20,21 bis-methylenedioxy-LS- pregimdieize-IIfi-oL-Jn a manner similar to that described in Example 16(B), treat a mixture of 17a,20;20, 21- bismethylenedioxy-1,5-pregnadiene-3B,1lfl-diol and the.3a'-.hydroxy epimer thereof (prepared as described in Example 21 (B)) with methanolic-sulfuric acid. Isolate the resultant product in the described manner to obtain a mixture comprising 3fl-methoxy-17a,20;20,21-bis-methylenedioxy-l,5-pregnadiene-115-01 and the 3a-methoxy epimer thereof.

(B) 3 methoxy 1,5 pregnaa'iene-I1/3,17a,21-tri0l-20- 0ne.In a manner similar to that described in Example 21(0), treat the epimeric mixture prepared in Example 27(A) with formic acid and perchloric acid. Isolate the resultant product in the described manner to obtain a mixture of 3,8-methoxy-1,5-pregnadiene-11,8,17u,21-triol- 20-one and the 3a-methoxy epimer thereof. Crystallize the epimeric mixture from methanol to obtain a precipitate of 3 fi-methoxy- 1,5 -pregnadiene-1 118, l7a,2 1-triol-20-one.

Concentrate the methanol filtrate to a residue. Chromat-' ograph the residue on Florisil, eluting with methylene chloride containing increasing amounts of methanol. Combine like fractions and concentrate the combined fractions to a residue comprising 3a-methoxy-1,5-pregnadiene- 11/3,17a,21 trio1-20-one. Purify by crystallization from methanol.

EXAMPLE 28 3-meth0xy-9a,1I/K-dichl0r0-1,5-pregnadiene-17u-0l- 20-0ne 1 7-acetate In a manner similar to that described in Example 14, react 911,11/3 dichloro-1,5-pregnadiene-3B,17u-diol-20-one 17-acetate in tetrahydrofuran with sodium hydride and methyliodide. Isolate and purify the resultant product in the described manner to give 3B-methoxy-9u,1lfi-dichloro- 1,5-pregnadiene-17a-ol-20-0ne 17-acetate.

EXAMPLE 29 LS-pregnadiene-i] 15,1 7a,21-tetr0l-20-one 3,21-diesters (A) 1,5 pregmzdiene-3JI,8,17a,21-tetrol-20-0ne 3,21- iizzcetate.Dissolve l g. of 1,5-pregnadiene-3fl,1118,17a, ZI-tetrol-ZO-one in 10 ml. of pyridine and 5 ml. of acetic anhydride. Allow the solution to stand at 25% C. for 8 iours; then add 1 m1. of Water. Pour the reaction mixture nto ice cold hydrochloric acid and extract the aqueous nixture with methylene chloride. Wash the combined exracts to neutrality with Water, dry over magnesium sulfate and evaporate to a residue in vacuo comprising 1,5- )regnadiene-3B,1 1fi,l7a,21-tetrol-20-one 3,2l-diacetate.

In a similar manner, 1,5 pregnadiene-3a,11B,17a,21- etrol-ZO-one 3,21-diacetate is prepared from the correponding 3u-hydroxy compound by reaction with acetic aniy-dride in pyridine.

(B) 15-pregnazliene-3JIBJ 7a,2]-teZr0l-20-0ne 3,21-divenzoale-React each of l,5-pregnadiene-3fi,11,8,17a,21- etrol-20-one and l,5-pregnadiene-3a,ll,8,17a,21-tetrol-20- me with benzoyl chloride in pyridine in the manner decri-bed in Example 3(D). Isolate the respective resultant roducts in the manner described to obtain 1,5-pregnalime-36,1lfi,17a,21-tetrol-20-one 3,2l-dibenzoate and 1,5- regnadiene-3u,l 1fi,17a,2l-tetrol-20-one 3,2l-dibenzoate.

In a manner similar to that described above in proedures A and B, each of the compounds prepared in Exmples 21 and 22 are converted to their respective 3,21- iacetate and 3,21-dibenzoate esters.

EXAMPLE 30 (A) 90: flur0-16a-methyl-1 7a,20;20,21-biS-m61hylnefoxy-1,S-pregnadiene-3,1l/3-diol 3 decanoate-The isoieric mixture of 9a-fluoro-16ot-methyl-17a,20;20,21-bisiethylenedioxy 1,5 pregnadiene-3/3,1l/3-di0l and 9auoro 16a methyl-17a,20;20,2l-bis-methylenedioxy-l, -pregnadiene-3a,11;3-diol (prepared as described in Exmple 22) is separated into the respective 3aand 3/3-hyroxy epimers in a maner similar to that described in EX- mple 21(B), i.e., by chromatography of the epimeric iixture on alumina, eluting with benzene containing inreasing amount of ether.

In a manner similar to that described in Example 3(E), eat each of x-fluoro- 1 6a-methy1- 1 7a,20;20,2 1 -bis-methylenedioxy-1,5-pregnadiene-3B,11,8-diol and a-filJOlO-l 6ot-methyl-1 7a,20;20,2l-bis-methylenedioxy- 1 ,S-pregnadiene, 3 a,1 1 fl-diol to obtain, respectively, 9ot-fiuoro-16a-methyl-L5-pregnadienes 36,11[3,17a,2l-tetrol-20-one 3-decanoate and 9afluoro-l6ot-methyl-1,5-pregnadiene-3fl,l1B,17a,21 tetrol- 20-one 3-decanoate.

(C) 9a-flu0 r0-16oc-methyl-I,S-pregnadiene 3,115,170, 21 -tetr0l-20-on\e 3-decan0wte 21-acetate.-In a manner similar to that described in Example 3(A), treat each of 9a-fluoro-16a-methyl-1,5-pregnadiene-3fl,115,170,

21-tetrol-20-one 3-decanoate and 9a-fluoro-16a-methyl-1,5-pregnadiene-3a,11 8,

17u,2l-tetrol-20-one 3-decanoate With acetic anhydride in pyridine and isolate the resultant product in the described manner to give, respectively, cfluoro-16u-methyl-1 ,5-pregnadiene-3 ,8,1 16, :,21 tetrol- 20-one 3-decanoate 21-ace-tate and 9cc-fl11OI0-160t-1'I16thYl- 1,5-pregnadiene-3a,l1fi,17a,21-tetrol-20-one 3 decanoate 21-acetate.

EXAMPLE 31 3-esters of 9a-1IB-dichl0r0-1,S-pregnadiene-iI 7adz'ol-ZO-one 17-ace1tate (A) In a manner similar to that described in Example 3(A), react 90;,11,8-dichloro-1,5-pregnadiene-3fl,17a-diol- 20-one l7-acetic with acetic acid in pyridine. Isolate and purify the resultant product in the described manner to obtain 906,11,B-dichloro-1,5-pregnadiene-3B,17a-diol 20- one diacetate.

By substituting propionic anhydride for acetic anhydride in the above procedure, there is obtained 9a,l1,8- dichloro-1,5-pregnadiene-3fl,17ot-diol-20-one 3-propionate 17-acetate.

(B) In a manner similar to that described in Example 3(D), react 904,1lfi-dichloro-1,5-pregnadiene-3B,17a-diol- 20-one 17-acetate With benzoyl chloride in pyridine to obtain 911,1lfi-dichloro-1,5-pregnadiene-3/3,17u-diol-20 one 3 benzoate 17-acetate.

In the above procedures (A) and (B) by substituting 9a, 1lfl-dichloro-1,5-pregnadiene-3 uc,170t-(llOl-20-OI18 17-acetate for 9a,1lfl-dichloro-1,5-pregnadiene-3fi,17a-diol-20- one 17-acetate, there may be obtained the respective 3ozesters, i.e., 9a,1lfi-dichloro-1,5-pregnadiene-3a,17a-diol- 20-one diacetate, 9a,1lli-dichloro-l,5-pregnadiene-3a,l7otdiol-20-one 3-propionate 17-acetate, and 9a,11B-dichlorol,5-pregnadiene-3 x,l7ot-dio l-20-one 3 benzoate 17 acetate.

EXAMPLE 32 1,5-p regnadicne-35J 7a-diol-20-one-3-acetate 17-capr0'ate (A) 1,5-pregrradiene-3fl17a-di0l-20-0ne 3-aceta'te.--In a manner similar to that described in Example 3(A), react 1,S-pregnadiene-3/3,17a-diol-20-one with acetic anhydride in pyridine at 25 C. to obtain 1,5-pregnadiene-3fl, 17a-diol-20-one 3-acetate.

Similarly, reaction of 1,5-pregnadiene-3a,l7ot-diol-20- one with acetic anhydride in pyridine as described above yields 1,5-pregnadiene-3a,17a-diol-20-one 3-acetate.

(B) 1,5-pregna'diene-3BJ7a-idiol-2o-one 3-acetaite 17- capr0ate.--To a solution of 1 g. of 1,5-pregnadiene-3/3, 17a-diol-20-one 3-acetate in 10 ml. of N-caproic acid through which argon gas is bubbled, add under anhydrous conditions 2 ml. of trifluoroacetic anhydride. Gently bubble the argon gas through the reaction mixture at a temperature of 85-90 C. for 55 minutes. Pour the reac tion mixture into ice Water and extract with methylene chloride. Extract the combined methylene chloride extracts With 3% sodium hydroxide and finally with water. Evaporate the organic layer to a residue and dissolve the residue in hexane and chromatograph on Florisil, eluting with ether containing increasing amounts of hexane. Combine the like fractions and evaporate to a residue comprising 1,5-pregnadiene-3/3,17a-diol-20-one 3-acetate 17-caproate. Purify by crystallization from ether-hexane.

Similarly, by substituting 1,5-pregnadiene-3u,17rx-diol 20-one 3-acetate for 1,5-pregnadiene-3fl,17tx-diol-20-one 3-acetate in the above procedure, there is obtained 1,5- regnadiene-Ba,l7a-diol-20-one 3-acetate 17-caproate.

We claim: 1. A compound selected from the group consisting of 3-hydroxy-1,5-bis-dehydro-steroids of the folowing structural formula:

wherein A is a member selected from the group consisting of hydrogen, (H,u-lower alkyl), (H,/3-lower alkyl) lower alkylene, (I-La-hYdIOXY), and (H,OL-1OWCI alkanoyloxy); B is a member selected from the group consisting of hydrogen, lower alkyl, and halogen; R is a member selected from the group consisting of hydrogen lower alkyl and acyl; Y is a member selected from the group consisting of hydrogen, keto, (H, 8OR (H,uOR and (I-LB-halogen), R being a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consitsing of hydrogen and halogen, and X is hydrogen when Y is a member selected from the group consisting of hydrogen and (H,aOH), and X is halogen when Y is (H,,8-halogen), and X and Y together are members of the group consisting of an epoxy and a double bond; and Z is a member selected from the group consisting of CH2Q OR" (3:0 0 (3...1), and R" being a member selected from the group consisting of hydrogen and an acid radical of a carboxylic acid having up to 18 carbon atoms; D being a member selected from the group consisting ofhydrogen, lower alkyl, ethinyl, halogeno-ethinyl, and alkyl-ethinyl; V being a member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy; and Q is a member selected from the group consisting of hydrogen, hydroxy, acyloxy, and halogen.

2. 17a-lower alkyl-1,5,-androstadiene-3,17/3-diol.

3. Hot-methyl-1,5-androstadiene-3fl,l7B-diol.

4. 17a-methyl-1,5-androstadiene-311,17B-di0l.

5. 3-OR-17u-methyl-l,S-androstadiene-175-01; wherein R is an acid radical of a carboxylic acid having up to 18 carbon atoms.

6. 17a-methyl-1,5-androstadiene 3,13,17f3-diol 3 decanoate.

7. 1,5 -pregnadiene-3 13,1 1 B, 17a,2 l-tetrol-ZO-one.

8. 1,5-pregnadiene-3 a,11fi,17a,21-tetrol-20-one.

9. In the process of preparing a 3-hydroxy-A -steroid of the following formula:

wherein A is a member selected from the group consisting of hydrogen, (H,OL-1OWCI' alkyl), (H,B-lower alkyl), lower alkylene, (H,a-hydroxy), and (H,d-1OW1' alkanoyloxy); B is a member selected from the group consisting of hydrogen, lower alkyl and halogen; R is a member selected from the group consisting of hydrogen, lower alkyl and acyl; Y is a member selected from the group consisting of hydrogen, keto, (H,,BOR (H,aOR and (lip-halogen), R being a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consisting of hydrogen and halogen, and X is hydrogen when Y is a member selected from the group consisting of hydrogen and (H,aOH), and X is halogen when Y is (H, 3-halogen) and X and Y together are members of the group consisting of an epoxy and a double bond; and Z is a member selected from the group consisting of CHzQ R" being a member selected from the group consisting of hydrogen and an acid radical of a carboxylic acid having up to 18 carbon atoms; D being a member selected from the group consisting of hydrogen, lower alkyl, ethinyl, halogeno-ethinyl, and alkyl-ethinyl; V being a member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy; and Q is a member selectedfrom the group consisting of hydrogen, hydroxy, acyloxy, and halogen; the step which comprises reacting a 3-keto- A -steroid of the following formula:

if. on

wherein A, B, X, Y and Z are as defined hereinabove and wherein all reactive ketones other than at C-3 are protected by ketone derivatives, with a reducing reagent selected from the group consisting of an alkali metal aluminum hydrde, an alkali metal borohydride, and a metal alkoxide in the corresponding alkanol.

10. The process for preparing 17a-methyl-1,5-androstadiene-3fl,17B-diol which comprises reacting 17a-methyl- 1,5-androstadiene-17p-ol-3-one with a reagent of the group consisting of an alkali metal aluminum hydride, an alkali metal borohydride, and a metal alkoxide in the corresponding alkanol.

11. The process for preparing 17a-methyl-1,5-androstadiene-3B,17,3-diol which comprises reacting 17a-methyl- 1,5-androstadiene-l7 8-ol-3-one with sodium borohydride.

References Cited UNITED STATES PATENTS 3/1964 Tanabe et al. 260-3974 3/ 1964 Shapiro et a1 260397.4

OTHER REFERENCES Loewenthal, Tetrahedron, vol. 6, No. 4, pp. 269-303, June 1959, pp. 281-283.

LEWIS GOTTS, Primary Examiner.

H. A. FRENCH, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,332 ,967 July 25 1967 Eugene P. Oliveto et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3 line 74 for "3 3,11 8,7a" read 3 3,11 5,17 m

column 13, line 44, for "5-androstadiene" read 1,5-androstadiene column 15 line 66 for "15 B-methyl" read 16 B- methyl column 18 line 8 for "16 B-ethyl" read 16 6- methyl line 46, for "16 B-ethyl read 16 B-methyl column 22, lines 26 and 27, for "17-methylenedioxy", each occurrence, read 17-ethy1enedi0xy column 27, line 72, for "3 5,17 a,2lone" read -1 3 [3,17 u,2l-triol-20one column 32 line 3 for "3 5,11 5,17 a" read 3q,11 6,17 d column 33,

lines 6 to 15 the formula should appear as shown below instead of as in the patent:

Signed and sealed this 9th day of July 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-HYDROXY-1,5-BIS-DEHYDRO-STEROIDS OF THE FOLLOWING STRUCTURAL FORMULA: 